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1
Ohno, Shiho, Noriyoshi Manabe, Takumi Yamaguchi, Jun Uzawa, and Yoshiki Yamaguchi. "Ribitol in Solution Is an Equilibrium of Asymmetric Conformations." Molecules 26, no. 18 (September 8, 2021): 5471. http://dx.doi.org/10.3390/molecules26185471.
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Ribitol (C5H12O5), an acyclic sugar alcohol, is present on mammalian α-dystroglycan as a component of O-mannose glycan. In this study, we examine the conformation and dynamics of ribitol by database analysis, experiments, and computational methods. Database analysis reveals that the anti-conformation (180°) is populated at the C3–C4 dihedral angle, while the gauche conformation (±60°) is seen at the C2–C3 dihedral angle. Such conformational asymmetry was born out in a solid-state 13C-NMR spectrum of crystalline ribitol, where C1 and C5 signals are unequal. On the other hand, solution 13C-NMR has identical chemical shifts for C1 and C5. NMR 3J coupling constants and OH exchange rates suggest that ribitol is an equilibrium of conformations, under the influence of hydrogen bonds and/or steric hinderance. Molecular dynamics (MD) simulations allowed us to discuss such a chemically symmetric molecule, pinpointing the presence of asymmetric conformations evidenced by the presence of correlations between C2–C3 and C3–C4 dihedral angles. These findings provide a basis for understanding the dynamic structure of ribitol and the function of ribitol-binding enzymes.
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Kang, Hyun-Seo, and Michael Sattler. "Capturing dynamic conformational shifts in protein–ligand recognition using integrative structural biology in solution." Emerging Topics in Life Sciences 2, no. 1 (April 20, 2018): 107–19. http://dx.doi.org/10.1042/etls20170090.
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In recent years, a dynamic view of the structure and function of biological macromolecules is emerging, highlighting an essential role of dynamic conformational equilibria to understand molecular mechanisms of biological functions. The structure of a biomolecule, i.e. protein or nucleic acid in solution, is often best described as a dynamic ensemble of conformations, rather than a single structural state. Strikingly, the molecular interactions and functions of the biological macromolecule can then involve a shift between conformations that pre-exist in such an ensemble. Upon external cues, such population shifts of pre-existing conformations allow gradually relaying the signal to the downstream biological events. An inherent feature of this principle is conformational dynamics, where intrinsically disordered regions often play important roles to modulate the conformational ensemble. Unequivocally, solution-state NMR spectroscopy is a powerful technique to study the structure and dynamics of such biomolecules in solution. NMR is increasingly combined with complementary techniques, including fluorescence spectroscopy and small angle scattering. The combination of these techniques provides complementary information about the conformation and dynamics in solution and thus affords a comprehensive description of biomolecular functions and regulations. Here, we illustrate how an integrated approach combining complementary techniques can assess the structure and dynamics of proteins and protein complexes in solution.
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Qu, Kun, Qiuluan Chen, Katarzyna A. Ciazynska, Banghui Liu, Xixi Zhang, Jingjing Wang, Yujie He, et al. "Engineered disulfide reveals structural dynamics of locked SARS-CoV-2 spike." PLOS Pathogens 18, no. 7 (July 29, 2022): e1010583. http://dx.doi.org/10.1371/journal.ppat.1010583.
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The spike (S) protein of SARS-CoV-2 has been observed in three distinct pre-fusion conformations: locked, closed and open. Of these, the function of the locked conformation remains poorly understood. Here we engineered a SARS-CoV-2 S protein construct “S-R/x3” to arrest SARS-CoV-2 spikes in the locked conformation by a disulfide bond. Using this construct we determined high-resolution structures confirming that the x3 disulfide bond has the ability to stabilize the otherwise transient locked conformations. Structural analyses reveal that wild-type SARS-CoV-2 spike can adopt two distinct locked-1 and locked-2 conformations. For the D614G spike, based on which all variants of concern were evolved, only the locked-2 conformation was observed. Analysis of the structures suggests that rigidified domain D in the locked conformations interacts with the hinge to domain C and thereby restrains RBD movement. Structural change in domain D correlates with spike conformational change. We propose that the locked-1 and locked-2 conformations of S are present in the acidic high-lipid cellular compartments during virus assembly and egress. In this model, release of the virion into the neutral pH extracellular space would favour transition to the closed or open conformations. The dynamics of this transition can be altered by mutations that modulate domain D structure, as is the case for the D614G mutation, leading to changes in viral fitness. The S-R/x3 construct provides a tool for the further structural and functional characterization of the locked conformations of S, as well as how sequence changes might alter S assembly and regulation of receptor binding domain dynamics.
4
Guo, Qing, Yufan He, and H. Peter Lu. "Interrogating the activities of conformational deformed enzyme by single-molecule fluorescence-magnetic tweezers microscopy." Proceedings of the National Academy of Sciences 112, no. 45 (October 28, 2015): 13904–9. http://dx.doi.org/10.1073/pnas.1506405112.
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Characterizing the impact of fluctuating enzyme conformation on enzymatic activity is critical in understanding the structure–function relationship and enzymatic reaction dynamics. Different from studying enzyme conformations under a denaturing condition, it is highly informative to manipulate the conformation of an enzyme under an enzymatic reaction condition while monitoring the real-time enzymatic activity changes simultaneously. By perturbing conformation of horseradish peroxidase (HRP) molecules using our home-developed single-molecule total internal reflection magnetic tweezers, we successfully manipulated the enzymatic conformation and probed the enzymatic activity changes of HRP in a catalyzed H2O2–amplex red reaction. We also observed a significant tolerance of the enzyme activity to the enzyme conformational perturbation. Our results provide a further understanding of the relation between enzyme behavior and enzymatic conformational fluctuation, enzyme–substrate interactions, enzyme–substrate active complex formation, and protein folding–binding interactions.
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Ludwiczak, Jan, Ewa Szczęsna, Antônio Marinho da Silva Neto, Piotr Cieplak, Andrzej A. Kasprzak, and Adam Jarmuła. "Interactions between motor domains in kinesin-14 Ncd — a molecular dynamics study." Biochemical Journal 476, no. 17 (September 10, 2019): 2449–62. http://dx.doi.org/10.1042/bcj20190484.
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Abstract Minus-end directed, non-processive kinesin-14 Ncd is a dimeric protein with C-terminally located motor domains (heads). Generation of the power-stroke by Ncd consists of a lever-like rotation of a long superhelical ‘stalk’ segment while one of the kinesin's heads is bound to the microtubule. The last ∼30 amino acids of Ncd head play a crucial but still poorly understood role in this process. Here, we used accelerated molecular dynamics simulations to explore the conformational dynamics of several systems built upon two crystal structures of Ncd, the asymmetrical T436S mutant in pre-stroke/post-stroke conformations of two partner subunits and the symmetrical wild-type protein in pre-stroke conformation of both subunits. The results revealed a new conformational state forming following the inward motion of the subunits and stabilized with several hydrogen bonds to residues located on the border or within the C-terminal linker, i.e. a modeled extension of the C-terminus by residues 675–683. Forming of this new, compact Ncd conformation critically depends on the length of the C-terminus extending to at least residue 681. Moreover, the associative motion leading to the compact conformation is accompanied by a partial lateral rotation of the stalk. We propose that the stable compact conformation of Ncd may represent an initial state of the working stroke.
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Bierzyński, A. "Methods of peptide conformation studies." Acta Biochimica Polonica 48, no. 4 (December 31, 2001): 1091–99. http://dx.doi.org/10.18388/abp.2001_3870.
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In solution most of the peptides assume multiple flexible conformations. Determination of the dominant conformers and evaluation of their populations is the aim of peptide conformation studies, in which theoretical and experimental methods play complementary roles. Molecular dynamics or Monte Carlo methods are quite effective in searching the conformational space accessible to a peptide but they are not able to estimate, precisely enough, the populations of various conformations. Therefore, they must be supplemented by experimental data. In this paper, a short review of the experimental methods, most widely used in peptide conformational studies, is presented. Among them NMR plays the leading role. Valuable information is also obtained from hydrogen exchange, fluorescence resonance energy transfer, and circular dichroism measurements. The advantages and shortcomings of these methods are discussed.
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Gaalswyk, Kari, and Christopher N. Rowley. "An explicit-solvent conformation search method using open software." PeerJ 4 (May 31, 2016): e2088. http://dx.doi.org/10.7717/peerj.2088.
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Computer modeling is a popular tool to identify the most-probable conformers of a molecule. Although the solvent can have a large effect on the stability of a conformation, many popular conformational search methods are only capable of describing molecules in the gas phase or with an implicit solvent model. We have developed a work-flow for performing a conformation search on explicitly-solvated molecules using open source software. This method uses replica exchange molecular dynamics (REMD) to sample the conformational states of the molecule efficiently. Cluster analysis is used to identify the most probable conformations from the simulated trajectory. This work-flow was tested on drug molecules α-amanitin and cabergoline to illustrate its capabilities and effectiveness. The preferred conformations of these molecules in gas phase, implicit solvent, and explicit solvent are significantly different.
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Lin, Shawn H., Dacheng Zhao, Vivian Deng, Veronica K. Birdsall, Suzanne Ho, Olga Buzovetsky, Candice M. Etson, and Ishita Mukerji. "Integration Host Factor Binds DNA Holliday Junctions." International Journal of Molecular Sciences 24, no. 1 (December 29, 2022): 580. http://dx.doi.org/10.3390/ijms24010580.
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Integration host factor (IHF) is a nucleoid-associated protein involved in DNA packaging, integration of viral DNA and recombination. IHF binds with nanomolar affinity to duplex DNA containing a 13 bp consensus sequence, inducing a bend of ~160° upon binding. We determined that IHF binds to DNA Four-way or Holliday junctions (HJ) with high affinity regardless of the presence of the consensus sequence, signifying a structure-based mechanism of recognition. Junctions, important intermediates in DNA repair and homologous recombination, are dynamic and can adopt either an open or stacked conformation, where the open conformation facilitates branch migration and strand exchange. Using ensemble and single molecule Förster resonance energy transfer (FRET) methods, we investigated IHF-induced changes in the population distribution of junction conformations and determined that IHF binding shifts the population to the open conformation. Further analysis of smFRET dynamics revealed that even in the presence of protein, the junctions remain dynamic as fast transitions are observed for the protein-bound open state. Protein binding alters junction conformational dynamics, as cross correlation analyses reveal the protein slows the transition rate at 1 mM Mg2+ but accelerates the transition rate at 10 mM Mg2+. Stopped flow kinetic experiments provide evidence for two binding steps, a rapid, initial binding step followed by a slower step potentially associated with a conformational change. These measurements also confirm that the protein remains bound to the junction during the conformer transitions and further suggest that the protein forms a partially dissociated state that allows junction arms to be dynamic. These findings, which demonstrate that IHF binds HJs with high affinity and stabilizes junctions in the open conformation, suggest that IHF may play multiple roles in the processes of integration and recombination in addition to stabilizing bacterial biofilms.
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Mizutani, Tadashi, and Shigeyuki Yagi. "Linear tetrapyrroles as functional pigments in chemistry and biology." Journal of Porphyrins and Phthalocyanines 08, no. 03 (March 2004): 226–37. http://dx.doi.org/10.1142/s1088424604000210.
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1,19,21,24-tetrahydro-1,19-bilindione is the framework of pigments frequently found in nature, which includes biliverdin IX α, phytochromobilin and phycocyanobilin. 1,19-bilindiones have unique features such as (1) photochemical and thermal cis-trans isomerization, (2) excited energy transfer, (3) chiroptical properties due to the cyclic helical conformation, (4) redox activity, (5) coordination to various metals, and (6) reconstitution to proteins. 1,19-bilindione can adopt a number of conformations since it has exocyclic three double bonds and three single bonds that are rotatable thermally and photochemically. In solution, biliverdin and phycocyanobilin adopt a cyclic helical ZZZ, syn, syn, syn conformation, but other conformations are stabilized depending on the experimental conditions and substituents on the bilin framework. The conformational changes in 1,19-bilindiones are related to the biological functions of a photoreceptor protein, phytochrome. Structural and conformational studies of bilindiones are summarized both in solution and in protein. The conformational changes of bilins can be used for other functions such as a chirality sensor. The bilindiones and the zinc complexes of bilindiones can be employed as a chirality sensor due to the helically chiral structure and the dynamics of racemization of enantiomers. In this paper, we discuss the conformational equilibria and dynamics of bilindiones and its implications in photobiology and materials science.
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Verma, Rajni, Jonathan M. Ellis, and Katie R. Mitchell-Koch. "Dynamic Preference for NADP/H Cofactor Binding/Release in E. coli YqhD Oxidoreductase." Molecules 26, no. 2 (January 7, 2021): 270. http://dx.doi.org/10.3390/molecules26020270.
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YqhD, an E. coli alcohol/aldehyde oxidoreductase, is an enzyme able to produce valuable bio-renewable fuels and fine chemicals from a broad range of starting materials. Herein, we report the first computational solution-phase structure-dynamics analysis of YqhD, shedding light on the effect of oxidized and reduced NADP/H cofactor binding on the conformational dynamics of the biocatalyst using molecular dynamics (MD) simulations. The cofactor oxidation states mainly influence the interdomain cleft region conformations of the YqhD monomers, involved in intricate cofactor binding and release. The ensemble of NADPH-bound monomers has a narrower average interdomain space resulting in more hydrogen bonds and rigid cofactor binding. NADP-bound YqhD fluctuates between open and closed conformations, while it was observed that NADPH-bound YqhD had slower opening/closing dynamics of the cofactor-binding cleft. In the light of enzyme kinetics and structural data, simulation findings have led us to postulate that the frequently sampled open conformation of the cofactor binding cleft with NADP leads to the more facile release of NADP while increased closed conformation sampling during NADPH binding enhances cofactor binding affinity and the aldehyde reductase activity of the enzyme.
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Verma, Rajni, Jonathan M. Ellis, and Katie R. Mitchell-Koch. "Dynamic Preference for NADP/H Cofactor Binding/Release in E. coli YqhD Oxidoreductase." Molecules 26, no. 2 (January 7, 2021): 270. http://dx.doi.org/10.3390/molecules26020270.
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YqhD, an E. coli alcohol/aldehyde oxidoreductase, is an enzyme able to produce valuable bio-renewable fuels and fine chemicals from a broad range of starting materials. Herein, we report the first computational solution-phase structure-dynamics analysis of YqhD, shedding light on the effect of oxidized and reduced NADP/H cofactor binding on the conformational dynamics of the biocatalyst using molecular dynamics (MD) simulations. The cofactor oxidation states mainly influence the interdomain cleft region conformations of the YqhD monomers, involved in intricate cofactor binding and release. The ensemble of NADPH-bound monomers has a narrower average interdomain space resulting in more hydrogen bonds and rigid cofactor binding. NADP-bound YqhD fluctuates between open and closed conformations, while it was observed that NADPH-bound YqhD had slower opening/closing dynamics of the cofactor-binding cleft. In the light of enzyme kinetics and structural data, simulation findings have led us to postulate that the frequently sampled open conformation of the cofactor binding cleft with NADP leads to the more facile release of NADP while increased closed conformation sampling during NADPH binding enhances cofactor binding affinity and the aldehyde reductase activity of the enzyme.
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Cao, Thong M., and Michael R. King. "Stabilization of the Hinge Region of Human E-selectin Enhances Binding Affinity to Ligands Under Force." Cellular and Molecular Bioengineering 14, no. 1 (February 2021): 65–74. http://dx.doi.org/10.1007/s12195-021-00666-z.
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Abstract Introduction E-selectin is a member of the selectin family of cell adhesion molecules expressed on the plasma membrane of inflamed endothelium and facilitates initial leukocyte tethering and subsequent cell rolling during the early stages of the inflammatory response via binding to glycoproteins expressing sialyl LewisX and sialyl LewisA (sLeX/A). Existing crystal structures of the extracellular lectin/EGF-like domain of E-selectin complexed with sLeX have revealed that E-selectin can exist in two conformation states, a low affinity (bent) conformation, and a high affinity (extended) conformation. The differentiating characteristic of the two conformations is the interdomain angle between the lectin and the EGF-like domain. Methods Using molecular dynamics (MD) simulations we observed that in the absence of tensile force E-selectin undergoes spontaneous switching between the two conformational states at equilibrium. A single amino acid substitution at residue 2 (serine to tyrosine) on the lectin domain favors the extended conformation. Results Steered molecular dynamics (SMD) simulations of E-selectin and PSGL-1 in conjunction with experimental cell adhesion assays show a longer binding lifetime of E-selectin (S2Y) to PSGL-1 compared to wildtype protein. Conclusions The findings in this study advance our understanding into how the structural makeup of E-selectin allosterically influences its adhesive dynamics.
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Roh, Soung-Hun, Corey F. Hryc, Hyun-Hwan Jeong, Xue Fei, Joanita Jakana, George H. Lorimer, and Wah Chiu. "Subunit conformational variation within individual GroEL oligomers resolved by Cryo-EM." Proceedings of the National Academy of Sciences 114, no. 31 (July 14, 2017): 8259–64. http://dx.doi.org/10.1073/pnas.1704725114.
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Single-particle electron cryo-microscopy (cryo-EM) is an emerging tool for resolving structures of conformationally heterogeneous particles; however, each structure is derived from an average of many particles with presumed identical conformations. We used a 3.5-Å cryo-EM reconstruction with imposed D7 symmetry to further analyze structural heterogeneity among chemically identical subunits in each GroEL oligomer. Focused classification of the 14 subunits in each oligomer revealed three dominant classes of subunit conformations. Each class resembled a distinct GroEL crystal structure in the Protein Data Bank. The conformational differences stem from the orientations of the apical domain. We mapped each conformation class to its subunit locations within each GroEL oligomer in our dataset. The spatial distributions of each conformation class differed among oligomers, and most oligomers contained 10–12 subunits of the three dominant conformation classes. Adjacent subunits were found to more likely assume the same conformation class, suggesting correlation among subunits in the oligomer. This study demonstrates the utility of cryo-EM in revealing structure dynamics within a single protein oligomer.
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Lane, A. N., T. C. Jenkins, D. J. Brown, and T. Brown. "N.m.r. determination of the solution conformation and dynamics of the A.G mismatch in the d(CGCAAATTGGCG)2 dodecamer." Biochemical Journal 279, no. 1 (October 1, 1991): 269–81. http://dx.doi.org/10.1042/bj2790269.
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A.G base-paired mismatches that occur during replication are among the most difficult to detect by repair enzymes. Such purine.purine mispairs can exist in two conformations, one of which is stabilized by protons [Gao & Patel (1988) J. Am. Chem. Soc. 110, 5178-5182]. We have undertaken a 1H-n.m.r. and 31P-n.m.r. study of the mismatched dodecamer d(CGCAAATTGGCG)2 as a function of both temperature and pH to determine the conformational features of the A.G mismatch. At pH greater than 7 the mispaired bases are each in the anti conformation and are stacked in the B-like helix. As the pH is decreased, a second conformation becomes populated (apparent pKa approx. 5.9) with concomitant changes in the chemical shifts of protons of the mispaired bases and their nearest neighbours. Data from two-dimensional nuclear-Overhauser-enhancement spectroscopy show unequivocally that, at low pH, the dominant conformation is one in which the mismatched G residues are in the syn conformation and are hydrogen-bonded to the A residues that remain in the anti conformation. Residues not adjacent to the A.G sites are almost unaffected by the transition or the mispairing, suggesting considerable local flexibility of the unconstrained duplexes. Despite the bulging of the mispaired bases, the conformation of the A(anti).G(anti) duplex is very similar to the native dodecamer, whereas the AH+(anti).G(syn) duplex shows a greater variation in the backbone conformation at the mismatched site. According to the chemical shifts, the duplex retains twofold symmetry in solution. The equilibrium between the syn and anti conformations of G9/G21 is strongly dependent on pH, but only weakly dependent on temperature (delta H approx. 16 kJ.mol-1). The first-order rate constant for the transition is approx. 9 s-1 at 283 K and approx. 60 s-1 at 298 K, with an activation enthalpy of approx. 100 kJ.mol-1. The stabilization of the A(anti).G(syn) conformation by protons is consistent with models invoking N1 protonation of adenine. Using the derived glycosidic torsion angles we have used restrained molecular dynamics to build models of the neutral and protonated d(CGCAAATTGGCG)2 oligomers. The results confirm that the A(anti).G(anti) and AH+(anti).G(syn) conformations are favoured at high pH and low pH respectively, in accord with n.m.r. and single-crystal X-ray data.
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Savintseva, Liana A., Ilya S. Steshin, Alexander A. Avdoshin, Sergey V. Panteleev, Alexey V. Rozhkov, Ekaterina A. Shirokova, Grigory D. Livshits, et al. "Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane." Molecules 28, no. 3 (January 31, 2023): 1347. http://dx.doi.org/10.3390/molecules28031347.
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Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 μs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.
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Ramirez-Mondragon, Carlos A., Megin E. Nguyen, Jozafina Milicaj, Bakar A. Hassan, Frank J. Tucci, Ramaiah Muthyala, Jiali Gao, Erika A. Taylor, and Yuk Y. Sham. "Conserved Conformational Hierarchy across Functionally Divergent Glycosyltransferases of the GT-B Structural Superfamily as Determined from Microsecond Molecular Dynamics." International Journal of Molecular Sciences 22, no. 9 (April 28, 2021): 4619. http://dx.doi.org/10.3390/ijms22094619.
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It has long been understood that some proteins undergo conformational transitions en route to the Michaelis Complex to allow chemistry. Examination of crystal structures of glycosyltransferase enzymes in the GT-B structural class reveals that the presence of ligand in the active site triggers an open-to-closed conformation transition, necessary for their catalytic functions. Herein, we describe microsecond molecular dynamics simulations of two distantly related glycosyltransferases that are part of the GT-B structural superfamily, HepI and GtfA. Simulations were performed using the open and closed conformations of these unbound proteins, respectively, and we sought to identify the major dynamical modes and communication networks that interconnect the open and closed structures. We provide the first reported evidence within the scope of our simulation parameters that the interconversion between open and closed conformations is a hierarchical multistep process which can be a conserved feature of enzymes of the same structural superfamily. Each of these motions involves of a collection of smaller molecular reorientations distributed across both domains, highlighting the complexities of protein dynamic involved in the interconversion process. Additionally, dynamic cross-correlation analysis was employed to explore the potential effect of distal residues on the catalytic efficiency of HepI. Multiple distal nonionizable residues of the C-terminal domain exhibit motions anticorrelated to positively charged residues in the active site in the N-terminal domain involved in substrate binding. Mutations of these residues resulted in a reduction in negatively correlated motions and an altered enzymatic efficiency that is dominated by lower Km values with kcat effectively unchanged. The findings suggest that residues with opposing conformational motions involved in the opening and closing of the bidomain HepI protein can allosterically alter the population and conformation of the “closed” state, essential to the formation of the Michaelis complex. The stabilization effects of these mutations likely equally influence the energetics of both the ground state and the transition state of the catalytic reaction, leading to the unaltered kcat. Our study provides new insights into the role of conformational dynamics in glycosyltransferase’s function and new modality to modulate enzymatic efficiency.
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Košovan, Peter, Zuzana Limpouchová, and Karel Procházka. "Charge Distribution and Conformations of Weak Polyelectrolyte Chains in Poor Solvents." Collection of Czechoslovak Chemical Communications 73, no. 4 (2008): 439–58. http://dx.doi.org/10.1135/cccc20080439.
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In this work we study the effect of mobility of charges in annealed polyelectrolytes on their conformational behavior in poor solvents. A combination of molecular dynamics and Monte Carlo simulation techniques was used to take the dissociation into account. We investigated the relation between the conformation of the polyelectrolyte and the distribution of charges along the chain. The results suggest that in sufficiently poor solvents the local degree of charging differs significantly from the average. When a pearl-necklace conformation is formed, the degree of charging of the pearls is significantly lower than that of the strings. The redistribution of charges stabilizes the pearl-necklace conformation and enables the formation of asymmetric conformations with a single pearl at one chain end and a string at the other end.
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Li, Haiyan, Zanxia Cao, Guodong Hu, Liling Zhao, Chunling Wang, and Jihua Wang. "Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations." Technology and Health Care 29 (March 25, 2021): 103–14. http://dx.doi.org/10.3233/thc-218011.
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BACKGROUND: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations. OBJECTIVE: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models. METHODS: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations. RESULTS: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation. CONCLUSIONS: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.
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Ping, Jie, Pei Hao, Yi-Xue Li, and Jing-Fang Wang. "Molecular Dynamics Studies on the Conformational Transitions of Adenylate Kinase: A Computational Evidence for the Conformational Selection Mechanism." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/628536.
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Escherichia coliadenylate kinase (ADK) is a monomeric phosphotransferase enzyme that catalyzes reversible transfer of phosphoryl group from ATP to AMP with a large-scale domain motion. The detailed mechanism for this conformational transition remains unknown. In the current study, we performed long time-scale molecular dynamics simulations on both open and closed states of ADK. Based on the structural analyses of the simulation trajectories, we detected over 20 times conformational transitions between the open and closed states of ADK and identified two novel conformations as intermediate states in the catalytic processes. With these findings, we proposed a possible mechanism for the large-scale domain motion ofEscherichia coliADK and its catalytic process: (1) the substrate free ADK adopted an open conformation; (2) ATP bound with LID domain closure; (3) AMP bound with NMP domain closure; (4) phosphoryl transfer occurred with ATP, and AMP converted into two ADPs, and no conformational transition was detected in the enzyme; (5) LID domain opened with one ADP released; (6) another ADP released with NMP domain open. As both open and closed states sampled a wide range of conformation transitions, our simulation strongly supported the conformational selection mechanism forEscherichia coliADK.
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Campbell, Ashley C., Kyle M. Stiers, Julia S. Martin Del Campo, Ritcha Mehra-Chaudhary, Pablo Sobrado, and John J. Tanner. "Trapping conformational states of a flavin-dependent N-monooxygenase in crystallo reveals protein and flavin dynamics." Journal of Biological Chemistry 295, no. 38 (July 28, 2020): 13239–49. http://dx.doi.org/10.1074/jbc.ra120.014750.
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The siderophore biosynthetic enzyme A (SidA) ornithine hydroxylase from Aspergillus fumigatus is a fungal disease drug target involved in the production of hydroxamate-containing siderophores, which are used by the pathogen to sequester iron. SidA is an N-monooxygenase that catalyzes the NADPH-dependent hydroxylation of l-ornithine through a multistep oxidative mechanism, utilizing a C4a-hydroperoxyflavin intermediate. Here we present four new crystal structures of SidA in various redox and ligation states, including the first structure of oxidized SidA without NADP(H) or l-ornithine bound (resting state). The resting state structure reveals a new out active site conformation characterized by large rotations of the FAD isoalloxazine around the C1–′C2′ and N10–C1′ bonds, coupled to a 10-Å movement of the Tyr-loop. Additional structures show that either flavin reduction or the binding of NADP(H) is sufficient to drive the FAD to the in conformation. The structures also reveal protein conformational changes associated with the binding of NADP(H) and l-ornithine. Some of these residues were probed using site-directed mutagenesis. Docking was used to explore the active site of the out conformation. These calculations identified two potential ligand-binding sites. Altogether, our results provide new information about conformational dynamics in flavin-dependent monooxygenases. Understanding the different active site conformations that appear during the catalytic cycle may allow fine-tuning of inhibitor discovery efforts.
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Garaizar, Adiran, Ignacio Sanchez-Burgos, Rosana Collepardo-Guevara, and Jorge R. Espinosa. "Expansion of Intrinsically Disordered Proteins Increases the Range of Stability of Liquid–Liquid Phase Separation." Molecules 25, no. 20 (October 15, 2020): 4705. http://dx.doi.org/10.3390/molecules25204705.
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Proteins containing intrinsically disordered regions (IDRs) are ubiquitous within biomolecular condensates, which are liquid-like compartments within cells formed through liquid–liquid phase separation (LLPS). The sequence of amino acids of a protein encodes its phase behaviour, not only by establishing the patterning and chemical nature (e.g., hydrophobic, polar, charged) of the various binding sites that facilitate multivalent interactions, but also by dictating the protein conformational dynamics. Besides behaving as random coils, IDRs can exhibit a wide-range of structural behaviours, including conformational switching, where they transition between alternate conformational ensembles. Using Molecular Dynamics simulations of a minimal coarse-grained model for IDRs, we show that the role of protein conformation has a non-trivial effect in the liquid–liquid phase behaviour of IDRs. When an IDR transitions to a conformational ensemble enriched in disordered extended states, LLPS is enhanced. In contrast, IDRs that switch to ensembles that preferentially sample more compact and structured states show inhibited LLPS. This occurs because extended and disordered protein conformations facilitate LLPS-stabilising multivalent protein–protein interactions by reducing steric hindrance; thereby, such conformations maximize the molecular connectivity of the condensed liquid network. Extended protein configurations promote phase separation regardless of whether LLPS is driven by homotypic and/or heterotypic protein–protein interactions. This study sheds light on the link between the dynamic conformational plasticity of IDRs and their liquid–liquid phase behaviour.
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Xu, Xiaojun, Tao Yu, and Shi-Jie Chen. "Understanding the kinetic mechanism of RNA single base pair formation." Proceedings of the National Academy of Sciences 113, no. 1 (December 22, 2015): 116–21. http://dx.doi.org/10.1073/pnas.1517511113.
Full textAbstract:
RNA functions are intrinsically tied to folding kinetics. The most elementary step in RNA folding is the closing and opening of a base pair. Understanding this elementary rate process is the basis for RNA folding kinetics studies. Previous studies mostly focused on the unfolding of base pairs. Here, based on a hybrid approach, we investigate the folding process at level of single base pairing/stacking. The study, which integrates molecular dynamics simulation, kinetic Monte Carlo simulation, and master equation methods, uncovers two alternative dominant pathways: Starting from the unfolded state, the nucleotide backbone first folds to the native conformation, followed by subsequent adjustment of the base conformation. During the base conformational rearrangement, the backbone either retains the native conformation or switches to nonnative conformations in order to lower the kinetic barrier for base rearrangement. The method enables quantification of kinetic partitioning among the different pathways. Moreover, the simulation reveals several intriguing ion binding/dissociation signatures for the conformational changes. Our approach may be useful for developing a base pair opening/closing rate model.
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MIKHAILOV, Dmitri, J. Robert LINHARDT, and H. Kevin MAYO. "NMR solution conformation of heparin-derived hexasaccharide." Biochemical Journal 328, no. 1 (November 15, 1997): 51–61. http://dx.doi.org/10.1042/bj3280051.
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The solution conformation of homogeneous, heparin-derived hexasaccharide (residues A, B, C, D, E, F) has been investigated by using 1H-NMR spectroscopy. Intra-ring conformations have been defined by J-coupling constants and inter-proton nuclear Overhauser effects (NOEs), and the orientation of one ring with respect to the other has been defined by inter-ring NOEs. NOE-based conformational modelling has been done by using the iterative relaxation matrix approach (IRMA), restrained energy minimization to refine structures and to distinguish between minor structural differences and equilibria between various intra-ring forms. All glucosamine residues B, D and F are in the 4C1 chair conformation. The uronate (A) residue is mostly represented by the 1H2 form, whereas internal iduronates (C and E) exist in equilibrium between the chair and skewed boat forms. Deviations in some NOEs indicate a minor contribution of the 2H1 form to the A ring. Glycosidic dihedral angles, which define the overall oligosaccharide conformation, were further refined by combining in vacuo energy map calculations and restrained energy minimization in explicit solvent water. Conformational stability was further assessed by subjecting NOE and IRMA-derived structures to 600 ps of unrestrained molecular dynamics in explicit solvent.
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Andalib, Payam, Michael J. Wood, and Stephen J. Korn. "Control of Outer Vestibule Dynamics and Current Magnitude in the Kv2.1 Potassium Channel." Journal of General Physiology 120, no. 5 (October 29, 2002): 739–55. http://dx.doi.org/10.1085/jgp.20028639.
Full textAbstract:
In Kv2.1 potassium channels, changes in external [K+] modulate current magnitude as a result of a K+-dependent interconversion between two outer vestibule conformations. Previous evidence indicated that outer vestibule conformation (and thus current magnitude) is regulated by the occupancy of a selectivity filter binding site by K+. In this paper, we used the change in current magnitude as an assay to study how the interconversion between outer vestibule conformations is controlled. With 100 mM internal K+, rapid elevation of external [K+] from 0 to 10 mM while channels were activated produced no change in current magnitude (outer vestibule conformation did not change). When channels were subsequently closed and reopened in the presence of elevated [K+], current magnitude was increased (outer vestibule conformation had changed). When channels were activated in the presence of low internal [K+], or when K+ flow into conducting channels was transiently interrupted by an internal channel blocker, increasing external [K+] during activation did increase current magnitude (channel conformation did change). These data indicate that, when channels are in the activated state under physiological conditions, the outer vestibule conformation remains fixed despite changes in external [K+]. In contrast, when channel occupancy is lowered, (by channel closing, an internal blocker or low internal [K+]), the outer vestibule can interconvert between the two conformations. We discuss evidence that the ability of the outer vestibule conformation to change is regulated by the occupancy of a nonselectivity filter site by K+. Independent of the outer vestibule-based potentiation mechanism, Kv2.1 was remarkably insensitive to K+-dependent processes that influence current magnitude (current magnitude changed by <7% at membrane potentials between −20 and 30 mV). Replacement of two outer vestibule lysines in Kv2.1 by smaller neutral amino acids made current magnitude dramatically more sensitive to the reduction in K+ driving force (current magnitude changed by as much as 40%). When combined, these outer vestibule properties (fixed conformation during activation and the presence of lysines) all but prevent variation in Kv2.1 current magnitude when [K+] changes during activation. Moreover, the insensitivity of Kv2.1 current magnitude to changes in K+ driving force promotes a more uniform modulation of current over a wide range of membrane potentials by the K+-dependent regulation of outer vestibule conformation.
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Aljoundi, Aimen, Ahmed El Rashedy, Patrick Appiah-Kubi, and Mahmoud E. S. Soliman. "Coupling of HSP72 α-Helix Subdomains by the Unexpected Irreversible Targeting of Lysine-56 over Cysteine-17; Coevolution of Covalent Bonding." Molecules 25, no. 18 (September 16, 2020): 4239. http://dx.doi.org/10.3390/molecules25184239.
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Covalent inhibition has recently gained a resurgence of interest in several drug discovery areas. The expansion of this approach is based on evidence elucidating the selectivity and potency of covalent inhibitors when bound to particular amino acids of a biological target. The unexpected covalent inhibition of heat shock protein 72 (HSP72) by covalently targeting Lys-56 instead of Cys-17 was an interesting observation. However, the structural basis and conformational changes associated with this preferential coupling to Lys-56 over Cys-17 remain unclear. To resolve this mystery, we employed structural and dynamic analyses to investigate the structural basis and conformational dynamics associated with the unexpected covalent inhibition. Our analyses reveal that the coupling of the irreversible inhibitor to Lys-56 is intrinsically less dynamic than Cys-17. Conformational dynamics analyses further reveal that the coupling of the inhibitor to Lys-56 induced a closed conformation of the nucleotide-binding subdomain (NBD) α-helices, in contrast, an open conformation was observed in the case of Cys-17. The closed conformation maintained the crucial salt-bridge between Glu-268 and Lys-56 residues, which strengthens the interaction affinity of the inhibitor nearly identical to adenosine triphosphate (ADP/Pi) bound to the HSP72-NBD. The outcome of this report provides a substantial shift in the conventional direction for the design of more potent covalent inhibitors.
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Brenlla, Alfonso, Radoslaw P. Markiewicz, David Rueda, and Louis J. Romano. "Nucleotide selection by the Y-family DNA polymerase Dpo4 involves template translocation and misalignment." Nucleic Acids Research 42, no. 4 (November 21, 2013): 2555–63. http://dx.doi.org/10.1093/nar/gkt1149.
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Abstract Y-family DNA polymerases play a crucial role in translesion DNA synthesis. Here, we have characterized the binding kinetics and conformational dynamics of the Y-family polymerase Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) using single-molecule fluorescence. We find that in the absence of dNTPs, the binary complex shuttles between two different conformations within ∼1 s. These data are consistent with prior crystal structures in which the nucleotide binding site is either occupied by the terminal base pair (preinsertion conformation) or empty following Dpo4 translocation by 1 base pair (insertion conformation). Most interestingly, on dNTP binding, only the insertion conformation is observed and the correct dNTP stabilizes this complex compared with the binary complex, whereas incorrect dNTPs destabilize it. However, if the n+1 template base is complementary to the incoming dNTP, a structure consistent with a misaligned template conformation is observed, in which the template base at the n position loops out. This structure provides evidence for a Dpo4 mutagenesis pathway involving a transient misalignment mechanism.
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Anselmi, Cecilia, Marisanna Centini, Mirella Scotton, and Alessandro Sega. "Conformation and dynamics in solution of an N-quaternarized benzophenone derivative: a molecule active as UV filter." Canadian Journal of Chemistry 69, no. 6 (June 1, 1991): 913–18. http://dx.doi.org/10.1139/v91-135.
Full textAbstract:
The dynamics and conformation of N,N-dimethyl-N-|3-(benzoyl-4-phenoxy)|-N-n-dodecylammonium bromide, 1, have been established in two solvents (CDCl3 and DMSO-d6) by the use of 13C spin-lattice relaxation rates, non-selective and selective proton spin-lattice relaxation rates, and 1H–{1H} nuclear Overhauser enhancement (nOe) experiments. The data obtained are consistent with two main mean conformations for compound 1: a "linear" conformation in CDCl3 and a folded conformation in DMSO-d6 where the alkyl chain forms a loop toward the aromatic moiety. Key words: UV filter, carbon and proton relaxation rates, nuclear Overhauser enhancement experiments, solvent dependent conformations.
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Lei, Jiangtao, Xuanyao Li, Mengqiang Cai, Tianjing Guo, Dongdong Lin, Xiaohua Deng, and Yin Li. "Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L." International Journal of Molecular Sciences 23, no. 17 (September 3, 2022): 10100. http://dx.doi.org/10.3390/ijms231710100.
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Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser β-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249–267 and 268–282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.
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Dobrovolska, Olena, Øyvind Strømland, Ørjan Sele Handegård, Martin Jakubec, Morten L. Govasli, Åge Aleksander Skjevik, Nils Åge Frøystein, Knut Teigen, and Øyvind Halskau. "Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles." Molecules 26, no. 12 (June 12, 2021): 3607. http://dx.doi.org/10.3390/molecules26123607.
Full textAbstract:
The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.
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Roither, Bernhard, Chris Oostenbrink, Georg Pfeiler, Heinz Koelbl, and Wolfgang Schreiner. "Pembrolizumab Induces an Unexpected Conformational Change in the CC′-loop of PD-1." Cancers 13, no. 1 (December 22, 2020): 5. http://dx.doi.org/10.3390/cancers13010005.
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To improve cancer immunotherapy, a clearer understanding of key targets such as the immune checkpoint receptor PD-1 is essential. The PD-1 inhibitors nivolumab and pembrolizumab were recently approved by the FDA. The CC′-loop of PD-1 has been identified as a hotspot for drug targeting. Here, we investigate the influence of nivolumab and pembrolizumab on the molecular motion of the CC′-loop of PD-1. We performed molecular dynamics simulations on the complete extracellular domain of PD-1, in complex with PD-L1, and the blocking antibodies nivolumab and pembrolizumab. Conformations of the CC′-loop were analyzed unsupervised with the Daura et al. clustering algorithm and multidimensional scaling. Surprisingly, two conformations found were seen to correspond to the ‘open’ and ‘closed’ conformation of CC′-loop in apo-PD-1, already known from literature. Unsupervised clustering also surprisingly reproduced the natural ligand, PD-L1, exclusively stabilizing the ‘closed’ conformation, as also known from literature. Nivolumab, like PD-L1, was found to shift the equilibrium towards the ‘closed’ conformation, in accordance with the conformational selection model. Pembrolizumab, on the other hand, induced a third conformation of the CC′-loop which has not been described to date: Relative to the conformation ‘open’ the, CC′-loop turned 180° to form a new conformation which we called ‘overturned’. We show that the combination of clustering and multidimensional scaling is a fast, easy, and powerful method in analyzing structural changes in proteins. Possible refined antibodies or new small molecular compounds could utilize the flexibility of the CC′-loop to improve immunotherapy.
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MIKHAILOV, Dmitri, Kevin H. MAYO, Ioncho R. VLAHOV, Toshihiko TOIDA, Azra PERVIN, and Robert J. LINHARDT. "NMR solution conformation of heparin-derived tetrasaccharide." Biochemical Journal 318, no. 1 (August 15, 1996): 93–102. http://dx.doi.org/10.1042/bj3180093.
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The solution conformation of the homogeneous, heparin-derived tetrasaccharide ΔUA2S(1 → 4)-α-d-GlcNpS6S(1 → 4)-α-l-IdoAp2S(1 → 4)-α-d-GlcNpS6S (residues A, B, C and D respectively, where IdoA is iduronic acid) has been investigated by using 1H- and 13C-NMR. Ring conformations have been defined by J-coupling constants and inter-proton nuclear Overhauser effects (NOEs), and the orientation of one ring with respect to the other has been defined by inter-ring NOEs. NOE-based conformational modelling has been done by using the iterative relaxation matrix approach (IRMA), restrained molecular dynamics simulations and energy minimization to refine structures and to distinguish between minor structural differences and equilibria between various ring forms. Both glucosamine residues B and D are in the 4C1 chair conformation. The 6-O-sulphate group is oriented in the gauche–trans configuration in the D ring, whereas in the B ring the gauche–gauche rotomer predominates. Uronate (A) and iduronate (C) residues are mostly represented by 1H2 and 2S0 twisted boat forms, respectively, with small deviations in expected coupling constants and NOEs suggesting minor contributions from other A and C ring conformations.
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Zhang, Yiming, Zongzhou Ji, Xin Wang, Yi Cao, and Hai Pan. "Single–Molecule Study of DNAzyme Reveals Its Intrinsic Conformational Dynamics." International Journal of Molecular Sciences 24, no. 2 (January 7, 2023): 1212. http://dx.doi.org/10.3390/ijms24021212.
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DNAzyme is a class of DNA molecules that can perform catalytic functions with high selectivity towards specific metal ions. Due to its potential applications for biosensors and medical therapeutics, DNAzyme has been extensively studied to characterize the relationships between its biochemical properties and functions. Similar to protein enzymes and ribozymes, DNAzymes have been found to undergo conformational changes in a metal–ion–dependent manner for catalysis. Despite the important role the conformation plays in the catalysis process, such structural and dynamic information might not be revealed by conventional approaches. Here, by using the single–molecule fluorescence resonance energy transfer (smFRET) technique, we were able to investigate the detailed conformational dynamics of a uranyl–specific DNAzyme 39E. We observed conformation switches of 39E to a folded state with the addition of Mg2+ and to an extended state with the addition of UO22+. Furthermore, 39E can switch to a more compact configuration with or without divalent metal ions. Our findings reveal that 39E can undergo conformational changes spontaneously between different configurations.
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Wu, Si, Liu Hong, Yuqing Wang, Jieqiong Yu, Jie Yang, Jie Yang, Hong Zhang, and Sarah Perrett. "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." Proceedings of the National Academy of Sciences 117, no. 14 (March 20, 2020): 7814–23. http://dx.doi.org/10.1073/pnas.1914376117.
Full textAbstract:
Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an “ADP-like” undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70–Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.
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Mahboub, Radia. "Dynamics Simulation Studies of Solvation Effect on the Trans-Xylomollin Conformation." International Letters of Chemistry, Physics and Astronomy 13 (September 2013): 132–46. http://dx.doi.org/10.18052/www.scipress.com/ilcpa.13.132.
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The present work describes the solvation effect on the trans-xylomollin conformation. We have studied the trans-xylomollin conformations with the distance restraints using simulation calculations. Distance Restraint Molecular Dynamic (DR-MD) and Distance Restraint Langevin Dynamic (DR-LD) simulations of the trans-xylomollin were performed with an efficient program. The geometries, interaction energies, bonds, angles, and the Van der Waals (VDW) interactions were carried out in solution and gas phases. This comparative study shows that the trans-xylomollin acquires low total energy in solution using DR-MD method and stable conformation under the AMBER field. This molecule reaches its high stable conformation state in solution environment. The solvation effect is more important with DR-MD simulations. Our results are goods and in agreement with the used force field.
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Mahboub, Radia. "Dynamics Simulation Studies of Solvation Effect on the Trans-Xylomollin Conformation." International Letters of Chemistry, Physics and Astronomy 13 (May 3, 2013): 132–46. http://dx.doi.org/10.56431/p-694v14.
Full textAbstract:
The present work describes the solvation effect on the trans-xylomollin conformation. We have studied the trans-xylomollin conformations with the distance restraints using simulation calculations. Distance Restraint Molecular Dynamic (DR-MD) and Distance Restraint Langevin Dynamic (DR-LD) simulations of the trans-xylomollin were performed with an efficient program. The geometries, interaction energies, bonds, angles, and the Van der Waals (VDW) interactions were carried out in solution and gas phases. This comparative study shows that the trans-xylomollin acquires low total energy in solution using DR-MD method and stable conformation under the AMBER field. This molecule reaches its high stable conformation state in solution environment. The solvation effect is more important with DR-MD simulations. Our results are goods and in agreement with the used force field.
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Bennett, Ashley Lauren, and Rory Henderson. "HIV-1 Envelope Conformation, Allostery, and Dynamics." Viruses 13, no. 5 (May 7, 2021): 852. http://dx.doi.org/10.3390/v13050852.
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The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.
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Brouhard, Gary J., and Luke M. Rice. "The contribution of αβ-tubulin curvature to microtubule dynamics." Journal of Cell Biology 207, no. 3 (November 10, 2014): 323–34. http://dx.doi.org/10.1083/jcb.201407095.
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Microtubules are dynamic polymers of αβ-tubulin that form diverse cellular structures, such as the mitotic spindle for cell division, the backbone of neurons, and axonemes. To control the architecture of microtubule networks, microtubule-associated proteins (MAPs) and motor proteins regulate microtubule growth, shrinkage, and the transitions between these states. Recent evidence shows that many MAPs exert their effects by selectively binding to distinct conformations of polymerized or unpolymerized αβ-tubulin. The ability of αβ-tubulin to adopt distinct conformations contributes to the intrinsic polymerization dynamics of microtubules. αβ-Tubulin conformation is a fundamental property that MAPs monitor and control to build proper microtubule networks.
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Pasenkiewicz-Gierula, M., and T. Róg. "Conformations, orientations and time scales characterising dimyristoylphosphatidylcholine bilayer membrane. Molecular dynamics simulation studies." Acta Biochimica Polonica 44, no. 3 (September 30, 1997): 607–24. http://dx.doi.org/10.18388/abp.1997_4409.
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The results of molecular dynamics simulation of fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer membrane in the liquid-crystalline phase are presented. They show that the probability of a gauche conformation varies periodically along the chain with only a slight increase towards the end of the chain. However, the frequency of transition between conformations increases, due to a decrease in the lifetime of the trans conformation, along the chain. The average lifetimes for trans conformations are in the range of 1-2 x 10(-10) s and for gauche conformations in the range of 4-7 x 10(-11) s. The alpha-chain of the DMPC head group has mainly an extended conformation, due to predominantly trans conformation of alpha5 torsion. The rotational correlation time for the P-N vector is 3.7 ns. The C2-C1-O11-P fragment of the DMPC head group (theta1, alpha1, alpha2 torsions) is rigid while the P-O12-C11-C12 fragment (alpha3, alpha4, alpha5 torsions) is flexible. The lateral diffusion coefficient for DMPC self-diffusion in the membrane is 2 x 10(-7) cm2/s; the rate of transverse diffusion is the same. Large differences in the calculated rotational correlation times for the alpha-, beta-, gamma-chains and for the O21-C1 vector indicate that in the liquid-crystalline bilayer each segment of the DMPC molecule exhibits its own rotational freedom, in addition to its internal flexibility resulting from rotational isomerism. The results obtained in these calculations, although in general agreement with some experimental data, shed new light on the dynamical behaviour of phosphatidylcholine molecules in the bilayer membrane in the liquid-crystalline phase.
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Chen, Hui, Daniel M. Cohen, Dilshad M. Choudhury, Noriyuki Kioka, and Susan W. Craig. "Spatial distribution and functional significance of activated vinculin in living cells." Journal of Cell Biology 169, no. 3 (May 9, 2005): 459–70. http://dx.doi.org/10.1083/jcb.200410100.
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Conformational change is believed to be important to vinculin's function at sites of cell adhesion. However, nothing is known about vinculin's conformation in living cells. Using a Forster resonance energy transfer probe that reports on changes in vinculin's conformation, we find that vinculin is in the actin-binding conformation in a peripheral band of adhesive puncta in spreading cells. However, in fully spread cells with established polarity, vinculin's conformation is variable at focal adhesions. Time-lapse imaging reveals a gradient of conformational change that precedes loss of vinculin from focal adhesions in retracting regions. At stable or protruding regions, recruitment of vinculin is not necessarily coupled to the actin-binding conformation. However, a different measure of vinculin conformation, the recruitment of vinexin β by activated vinculin, shows that autoinhibition of endogenous vinculin is relaxed at focal adhesions. Beyond providing direct evidence that vinculin is activated at focal adhesions, this study shows that the specific functional conformation correlates with regional cellular dynamics.
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Paz, Aviv, Derek P. Claxton, Jay Prakash Kumar, Kelli Kazmier, Paola Bisignano, Shruti Sharma, Shannon A. Nolte, et al. "Conformational transitions of the sodium-dependent sugar transporter, vSGLT." Proceedings of the National Academy of Sciences 115, no. 12 (March 5, 2018): E2742—E2751. http://dx.doi.org/10.1073/pnas.1718451115.
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Sodium-dependent transporters couple the flow of Na+ ions down their electrochemical potential gradient to the uphill transport of various ligands. Many of these transporters share a common core structure composed of a five-helix inverted repeat and deliver their cargo utilizing an alternating-access mechanism. A detailed characterization of inward-facing conformations of the Na+-dependent sugar transporter from Vibrio parahaemolyticus (vSGLT) has previously been reported, but structural details on additional conformations and on how Na+ and ligand influence the equilibrium between other states remains unknown. Here, double electron–electron resonance spectroscopy, structural modeling, and molecular dynamics are utilized to deduce ligand-dependent equilibria shifts of vSGLT in micelles. In the absence and presence of saturating amounts of Na+, vSGLT favors an inward-facing conformation. Upon binding both Na+ and sugar, the equilibrium shifts toward either an outward-facing or occluded conformation. While Na+ alone does not stabilize the outward-facing state, gating charge calculations together with a kinetic model of transport suggest that the resting negative membrane potential of the cell, absent in detergent-solubilized samples, may stabilize vSGLT in an outward-open conformation where it is poised for binding external sugars. In total, these findings provide insights into ligand-induced conformational selection and delineate the transport cycle of vSGLT.
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Chen, Baohua, Sujit Basak, Peng Chen, Changcheng Zhang, Kay Perry, Songhai Tian, Clinton Yu, et al. "Structure and conformational dynamics of Clostridioides difficile toxin A." Life Science Alliance 5, no. 6 (March 15, 2022): e202201383. http://dx.doi.org/10.26508/lsa.202201383.
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Clostridioides difficile toxin A and B (TcdA and TcdB) are two major virulence factors responsible for diseases associated with C. difficile infection (CDI). Here, we report the 3.18-Å resolution crystal structure of a TcdA fragment (residues L843–T2481), which advances our understanding of the complete structure of TcdA holotoxin. Our structural analysis, together with complementary single molecule FRET and limited proteolysis studies, reveal that TcdA adopts a dynamic structure and its CROPs domain can sample a spectrum of open and closed conformations in a pH-dependent manner. Furthermore, a small globular subdomain (SGS) and the CROPs protect the pore-forming region of TcdA in the closed state at neutral pH, which could contribute to modulating the pH-dependent pore formation of TcdA. A rationally designed TcdA mutation that trapped the CROPs in the closed conformation showed drastically reduced cytotoxicity. Taken together, these studies shed new lights into the conformational dynamics of TcdA and its roles in TcdA intoxication.
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Dubovskii, Peter V., Kira M. Dubova, Gleb Bourenkov, Vladislav G. Starkov, Anastasia G. Konshina, Roman G. Efremov, Yuri N. Utkin, and Valeriya R. Samygina. "Variability in the Spatial Structure of the Central Loop in Cobra Cytotoxins Revealed by X-ray Analysis and Molecular Modeling." Toxins 14, no. 2 (February 18, 2022): 149. http://dx.doi.org/10.3390/toxins14020149.
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Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop (loop-2) were determined by X-ray crystallography. The “water” conformation of the loop was frequently observed. It was similar to the structure of loop-2 of numerous CTs, determined by either NMR spectroscopy in aqueous solution, or the X-ray method. The “membrane” conformation is rare one and, to date has only been observed by NMR for a single cytotoxin 1 from N. oxiana (CT1No) in detergent micelle. Both CT13Nn and CT1No are S-type CTs. Membrane-binding of these CTs probably involves an additional step—the conformational transformation of the loop-2. To confirm this suggestion, we conducted molecular dynamics simulations of both CT1No and CT13Nn in the Highly Mimetic Membrane Model of palmitoiloleoylphosphatidylglycerol, starting with their “water” NMR models. We found that the both toxins transform their “water” conformation of loop-2 into the “membrane” one during the insertion process. This supports the hypothesis that the S-type CTs, unlike their P-type counterparts, require conformational adaptation of loop-2 during interaction with lipid membranes.
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Ninaber, Alex, and J. M. Goodfellow. "DNA conformation and dynamics." Radiation and Environmental Biophysics 38, no. 1 (May 12, 1999): 23–29. http://dx.doi.org/10.1007/s004110050134.
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Luo, Liaofu. "Conformation dynamics of macromolecules." International Journal of Quantum Chemistry 32, no. 4 (October 1987): 435–50. http://dx.doi.org/10.1002/qua.560320404.
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Buckley, David P., Marie E. Migaud, and John J. Tanner. "Conformational Preferences of Pyridone Adenine Dinucleotides from Molecular Dynamics Simulations." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11866. http://dx.doi.org/10.3390/ijms231911866.
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Pyridone adenine dinucleotides (ox-NADs) are redox inactive derivatives of the enzyme cofactor and substrate nicotinamide adenine dinucleotide (NAD) that have a carbonyl group at the C2, C4, or C6 positions of the nicotinamide ring. These aberrant cofactor analogs accumulate in cells under stress and are potential inhibitors of enzymes that use NAD(H). We studied the conformational landscape of ox-NADs in solution using molecular dynamics simulations. Compared to NAD+ and NADH, 2-ox-NAD and 4-ox-NAD have an enhanced propensity for adopting the anti conformation of the pyridone ribose group, whereas 6-ox-NAD exhibits greater syn potential. Consequently, 2-ox-NAD and 4-ox-NAD have increased preference for folding into compact conformations, whereas 6-ox-NAD is more extended. ox-NADs have distinctive preferences for the orientation of the pyridone amide group, which are driven by intramolecular hydrogen bonding and steric interactions. These conformational preferences are compared to those of protein-bound NAD(H). Our results may help in identifying enzymes targeted by ox-NADs.
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Laugwitz, Jeannette M., Haleh H. Haeri, Anette Kaiser, Ulrike Krug, Dariush Hinderberger, Annette G. Beck-Sickinger, and Peter Schmidt. "Probing the Y2 Receptor on Transmembrane, Intra- and Extra-Cellular Sites for EPR Measurements." Molecules 25, no. 18 (September 10, 2020): 4143. http://dx.doi.org/10.3390/molecules25184143.
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The function of G protein-coupled receptors is intrinsically linked to their conformational dynamics. In conjugation with site-directed spin labeling, electron paramagnetic resonance (EPR) spectroscopy provides powerful tools to study the highly dynamic conformational states of these proteins. Here, we explored positions for nitroxide spin labeling coupled to single cysteines, introduced at transmembrane, intra- and extra-cellular sites of the human neuropeptide Y2 receptor. Receptor mutants were functionally analyzed in cell culture system, expressed in Escherichia coli fermentation with yields of up to 10 mg of purified protein per liter expression medium and functionally reconstituted into a lipid bicelle environment. Successful spin labeling was confirmed by a fluorescence assay and continuous wave EPR measurements. EPR spectra revealed mobile and immobile populations, indicating multiple dynamic conformational states of the receptor. We found that the singly mutated positions by MTSL ((1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl) methyl methanesulfonothioate) have a water exposed immobilized conformation as their main conformation, while in case of the IDSL (bis(1-oxyl-2,2,5,5-tetramethyl-3-imidazolin-4-yl) disulfide) labeled positions, the main conformation are mainly of hydrophobic nature. Further, double cysteine mutants were generated and examined for potential applications of distance measurements by double electron–electron resonance (DEER) pulsed EPR technique on the receptor.
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Samsonov, Sergey A., Stephan Theisgen, Thomas Riemer, Daniel Huster, and M. Teresa Pisabarro. "Glycosaminoglycan Monosaccharide Blocks Analysis by Quantum Mechanics, Molecular Dynamics, and Nuclear Magnetic Resonance." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/808071.
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Glycosaminoglycans (GAGs) play an important role in many biological processes in the extracellular matrix. In a theoretical approach, structures of monosaccharide building blocks of natural GAGs and their sulfated derivatives were optimized by a B3LYP6311ppdd//B3LYP/6-31+G(d) method. The dependence of the observed conformational properties on the applied methodology is described. NMR chemical shifts and proton-proton spin-spin coupling constants were calculated using the GIAO approach and analyzed in terms of the method's accuracy and sensitivity towards the influence of sulfation, O1-methylation, conformations of sugar ring, andωdihedral angle. The net sulfation of the monosaccharides was found to be correlated with the1H chemical shifts in the methyl group of the N-acetylated saccharides both theoretically and experimentally. Theωdihedral angle conformation populations of free monosaccharides and monosaccharide blocks within polymeric GAG molecules were calculated by a molecular dynamics approach using the GLYCAM06 force field and compared with the available NMR and quantum mechanical data. Qualitative trends for the impact of sulfation and ring conformation on the chemical shifts and proton-proton spin-spin coupling constants were obtained and discussed in terms of the potential and limitations of the computational methodology used to be complementary to NMR experiments and to assist in experimental data assignment.
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Caldararu, Octav, Vilhelm Ekberg, Derek T. Logan, Esko Oksanen, and Ulf Ryde. "Exploring ligand dynamics in protein crystal structures with ensemble refinement." Acta Crystallographica Section D Structural Biology 77, no. 8 (July 29, 2021): 1099–115. http://dx.doi.org/10.1107/s2059798321006513.
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Understanding the dynamics of ligands bound to proteins is an important task in medicinal chemistry and drug design. However, the dominant technique for determining protein–ligand structures, X-ray crystallography, does not fully account for dynamics and cannot accurately describe the movements of ligands in protein binding sites. In this article, an alternative method, ensemble refinement, is used on six protein–ligand complexes with the aim of understanding the conformational diversity of ligands in protein crystal structures. The results show that ensemble refinement sometimes indicates that the flexibility of parts of the ligand and some protein side chains is larger than that which can be described by a single conformation and atomic displacement parameters. However, since the electron-density maps are comparable and R free values are slightly increased, the original crystal structure is still a better model from a statistical point of view. On the other hand, it is shown that molecular-dynamics simulations and automatic generation of alternative conformations in crystallographic refinement confirm that the flexibility of these groups is larger than is observed in standard refinement. Moreover, the flexible groups in ensemble refinement coincide with groups that give high atomic displacement parameters or non-unity occupancy if optimized in standard refinement. Therefore, the conformational diversity indicated by ensemble refinement seems to be qualitatively correct, indicating that ensemble refinement can be an important complement to standard crystallographic refinement as a tool to discover which parts of crystal structures may show extensive flexibility and therefore are poorly described by a single conformation. However, the diversity of the ensembles is often exaggerated (probably partly owing to the rather poor force field employed) and the ensembles should not be trusted in detail.
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Tafi, A., Fabrizio Manetti, Federico Corelli, Stefano Alcaro, and Maurizio Botta. "Structural flexibility of hyaluronan oligomers as probed by molecular modelling." Pure and Applied Chemistry 75, no. 2-3 (January 1, 2003): 359–66. http://dx.doi.org/10.1351/pac200375020359.
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In the last few years, molecular modeling studies have been published that are devoted to a better understanding of the structural flexibility of hyaluronan (HA). Further conformational investigations, however, are needed on this polysaccharide, such as the application of statistical methods to perform enhanced one-step conformational analyses of its subunits. Moreover, the adjustment of assisted model building and energy refinement (AMBER) force field could provide the appropriate computational tool to study the interactions of HA and its derivatives with proteins. The present paper reports a combined Monte Carlo (MC) and molecular dynamics (MD) approach applied to the conformational study of HA, using an adjusted version of AMBER force field and the generalized Born solvent-accessible surface area (GB/SA) continuum solvation model. The MC approach turned out to be extremely effective to outline a conformational survey of the disaccharides constituting HA. Complete sets of conformations of the monomers were provided for the first time, some of which had never been predicted. MD technique, integrating the MC results, correctly reproduced the unusual stiffness of HA and predicted the existence of a minor skew-boat conformation of the β-d-glucuronic moiety. The computational approach, as a whole, improved the comprehension of the dynamic behavior of HA and offered a clear causal explanation of the relative dynamics of the glycosidic linkages.
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Gormal, Rachel S., Pranesh Padmanabhan, Ravikiran Kasula, Adekunle T. Bademosi, Sean Coakley, Jean Giacomotto, Ailisa Blum, et al. "Modular transient nanoclustering of activated β2-adrenergic receptors revealed by single-molecule tracking of conformation-specific nanobodies." Proceedings of the National Academy of Sciences 117, no. 48 (November 19, 2020): 30476–87. http://dx.doi.org/10.1073/pnas.2007443117.
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None of the current superresolution microscopy techniques can reliably image the changes in endogenous protein nanoclustering dynamics associated with specific conformations in live cells. Single-domain nanobodies have been invaluable tools to isolate defined conformational states of proteins, and we reasoned that expressing these nanobodies coupled to single-molecule imaging-amenable tags could allow superresolution analysis of endogenous proteins in discrete conformational states. Here, we used anti-GFP nanobodies tagged with photoconvertible mEos expressed as intrabodies, as a proof-of-concept to perform single-particle tracking on a range of GFP proteins expressed in live cells, neurons, and small organisms. We next expressed highly specialized nanobodies that target conformation-specific endogenous β2-adrenoreceptor (β2-AR) in neurosecretory cells, unveiling real-time mobility behaviors of activated and inactivated endogenous conformers during agonist treatment in living cells. We showed that activated β2-AR(Nb80) is highly immobile and organized in nanoclusters. The Gαs−GPCR complex detected with Nb37 displayed higher mobility with surprisingly similar nanoclustering dynamics to that of Nb80. Activated conformers are highly sensitive to dynamin inhibition, suggesting selective targeting for endocytosis. Inactivated β2-AR(Nb60) molecules are also largely immobile but relatively less sensitive to endocytic blockade. Expression of single-domain nanobodies therefore provides a unique opportunity to capture highly transient changes in the dynamic nanoscale organization of endogenous proteins.