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• W3157345013 abstract "Proteins are the molecular machines of living systems. Their dynamics are an intrinsic part of their evolutionary selection in carrying out their biological functions. Although the dynamics are more difficult to observe than a static, average structure, we are beginning to observe these dynamics and form sound mechanistic connections between structure, dynamics, and function. This progress is highlighted in case studies from myoglobin and adenylate kinase to the ribosome and molecular motors where these molecules are being probed with a multitude of techniques across many timescales. New approaches to time-resolved crystallography are allowing simple “movies” to be taken of proteins in action, and new methods of mapping the variations in cryo-electron microscopy are emerging to reveal a more complete description of life’s machines. The results of these new methods are aided in their dissemination by continual improvements in curation and distribution by the Protein Data Bank and their partners around the world. Proteins are the molecular machines of living systems. Their dynamics are an intrinsic part of their evolutionary selection in carrying out their biological functions. Although the dynamics are more difficult to observe than a static, average structure, we are beginning to observe these dynamics and form sound mechanistic connections between structure, dynamics, and function. This progress is highlighted in case studies from myoglobin and adenylate kinase to the ribosome and molecular motors where these molecules are being probed with a multitude of techniques across many timescales. New approaches to time-resolved crystallography are allowing simple “movies” to be taken of proteins in action, and new methods of mapping the variations in cryo-electron microscopy are emerging to reveal a more complete description of life’s machines. The results of these new methods are aided in their dissemination by continual improvements in curation and distribution by the Protein Data Bank and their partners around the world. Except at a temperature of absolute zero, which is impossible to achieve, molecules exhibit dynamic behavior. A scale from fast vibrational states to conformational changes to complete folding/unfolding events exist and can be observed in proteins and other biomacromolecules. Crystallography has celebrated over 100 years of visualizing the atomic structures of elements and compounds and about 60 years of doing the same for macromolecules and large biological complexes. More recently, cryo-electron microscopy has rocketed to the forefront of structure determination methods, also revealing atomic or near-atomic detail. These techniques, together with NMR have yielded almost 200,000 experimental determinations of the average positions of atoms in an astoundingly diverse set of proteins and nucleic acids and their complexes. Graphic artists’ renderings regularly grace the covers of journals. Perhaps because vision is one of the strongest senses of humans, we peruse these structures eagerly, hanging theories on them about how they work, defining atomic level mechanisms, and generating new hypothesis for further exploration. However, these macromolecules are not static at their physiological temperatures. We can often observe experimentally variations in structure and also sometimes time-dependent changes, i.e., dynamics. A disclaimer on use of the word dynamics should be given here. No one would argue with the idea that proteins with the same amino acid sequence exist in variety of states at some level of detail, and that at modest temperatures there are interconversions between these states, hence dynamic processes are taking place. Theories of induced fit (1Koshland D.E. Application of a theory of enzyme specificity to protein synthesis.Proc. Natl. Acad. Sci. U. S. A. 1958; 44: 98-104Crossref PubMed Google Scholar) and conformational selection (2Weikl T.R. Paul F. Conformational selection in protein binding and function.Protein Sci. 2014; 23: 1508-1518Crossref PubMed Scopus (57) Google Scholar) require a rearrangement of atoms in some kind of dynamic process. In this review, a broad definition of protein dynamics is used, including kinetic changes in particular structures and changes in populations within distributions of conformational states (3Frauenfelder H. Sligar S.G. Wolynes P.G. The energy landscapes and motions of proteins.Science. 1991; 254: 1598-1603Crossref PubMed Google Scholar). Not included here is another definition of protein dynamics that is more akin to protein turnover, with time-dependent changes in generation and degradation of pools of proteins. Our understanding of relationships between structure, dynamics, and function has been multidisciplinary, comprising work of theorists, computationalists, and experimentalists from physics, chemistry, and the biosciences. Thankfully there are some common mechanisms of communicating structure results in carefully defined ways. The value of scientific research is almost nothing if not shared with others; the communication of these atomic arrangements is paramount and yet publishing a list of numbers in a journal is not feasible beyond describing those in a modest-sized organic chemical, much less a protein. Protein crystallography did not exist before computers, at least not the “solving” part, and the value of storing the coordinates in electronic form seemed obvious. The idea to curate them and share them was not so obvious or even popular at first. Initially implemented at Brookhaven National Laboratory in 1971 (4Bernstein F.C. Koetzle T.F. Williams G.J. Meyer Jr., E.F. Brice M.D. Rodgers J.R. Kennard O. Shimanouchi T. Tasumi M. The Protein Data Bank. A computer-based archival file for macromolecular structures.Eur. J. Biochem. 1977; 80: 319-324Crossref PubMed Google Scholar, 5Rose P.W. Bi C. Bluhm W.F. Christie C.H. Dimitropoulos D. Dutta S. Green R.K. Goodsell D.S. Prlic A. Quesada M. Quinn G.B. Ramos A.G. Westbrook J.D. Young J. Zardecki C. et al.The RCSB Protein Data Bank: New resources for research and education.Nucleic Acids Res. 2013; 41: D475-482Crossref PubMed Scopus (343) Google Scholar, 6Berman H.M. Kleywegt G.J. Nakamura H. Markley J.L. The Protein Data Bank at 40: Reflecting on the past to prepare for the future.Structure. 2012; 20: 391-396Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) the Protein Data Bank (PDB) has come to be a positive example and a paradigm of community-based data sharing. The original PDB was designed to hold and distribute one set of coordinates per structure. In crystallography, these would typically be results of a refinement that worked to minimize the differences between measured diffraction patterns and those calculated from the set of atomic coordinates. For NMR they would be either a representative single structure or an ensemble of models, selected as example structures that met stringent requirements for being commensurate with the measured data. For cryo-EM these coordinates would be interpreted from carefully averaged images of single particles. In any case, there is still a challenge to add dynamically changing coordinates to the PDB, while dynamic processes are seen to be increasingly important for our understanding of protein function. Some examples of the quest for knowledge of protein dynamics from the authors’ own work and others are described below. These works illustrate some collective progress in observing protein dynamics and interpreting it in the context of biological function. The studies will be presented in order from small, fast dynamic events to larger, slower ones. Myoglobin, a small oxygen-carrying protein, the first protein to have its three-dimensional structure elucidated (7Kendrew J.C. Bodo G. Dintzis H.M. Parrish R.G. Wyckoff H. Phillips D.C. A three-dimensional model of the myoglobin molecule obtained by x-ray analysis.Nature. 1958; 181: 662-666Crossref PubMed Scopus (0) Google Scholar), was also immediately recognized to need dynamic components for its biological function, as there was no open pathway for the oxygen to get into and out of the protein without some rearrangement (8Kendrew J.C. Dickerson R.E. Strandberg B.E. Hart R.G. Davies D.R. Phillips D.C. Shore V.C. Structure of myoglobin: A three-dimensional Fourier synthesis at 2 A. resolution.Nature. 1960; 185: 422-427Crossref PubMed Scopus (820) Google Scholar). The shortest way in and out of the heme binding seemed to involve getting past the so-called distal histidine side chain, which in the crystal structures typically blocks the path (9Scott E.E. Gibson Q.H. Olson J.S. Mapping the pathways for O2 entry into and exit from myoglobin.J. Biol. Chem. 2001; 276: 5177-5188Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar) (Fig. 1). Myoglobin became a model system for all kinds of multidisciplinary studies in protein science, even being referred to as the “hydrogen atom” of biology by the prominent biophysicist, Hans Frauenfelder and colleagues (10Frauenfelder H. McMahon B.H. Fenimore P.W. Myoglobin: The hydrogen atom of biology and a paradigm of complexity.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 8615-8617Crossref PubMed Scopus (167) Google Scholar). The study of the dynamics of myoglobin is aided by the presence of an iron-containing heme cofactor that binds oxygen and other small compounds, such as the toxic molecule carbon monoxide. This group is also what makes myoglobin and hemoglobin red colored, giving a visible spectroscopic handle. The heme group thus provides opportunities for various spectroscopic experiments to probe the details of ligand binding and unbinding and sources of specificity for the biologically required oxygen. Even before the recent development of time-resolved crystallography experiments, a huge body of work existed to describe the dynamic binding and unbinding of small gaseous ligands to myoglobin and hemoglobin. In myoglobin, a flash of laser light can be used to rapidly break the covalent bond between the carbon of CO and the iron atom of the heme, termed photodissociation (11Austin R.H. Beeson K.W. Eisenstein L. Frauenfelder H. Gunsalus I.C. Dynamics of ligand binding to myoglobin.Biochemistry. 1975; 14: 5355-5373Crossref PubMed Google Scholar). Hans Frauenfelder and his collaborators in a series of papers experimentally identified the number and kinds of energy barriers that the CO had to overcome to rebind to the iron atom. Heterogeneity in the conformations of the protein manifested as nonexponential rebinding events, in which different substates of the system have different intrinsic rates and do not follow one classical exponential process. Later work (12Nienhaus G.U. Mourant J.R. Chu K. Frauenfelder H. Ligand binding to heme proteins: The effect of light on ligand binding in myoglobin.Biochemistry. 1994; 33: 13413-13430Crossref PubMed Google Scholar, 13Meuwly M. Becker O.M. Stote R. Karplus M. NO rebinding to myoglobin: A reactive molecular dynamics study.Biophys. Chem. 2002; 98: 183-207Crossref PubMed Scopus (97) Google Scholar) showed relaxation of the protein is crucial for the escape of the ligand from the pocket, as was suggested earlier by Friedman and colleagues (14Friedman J.M. Scott T.W. Fisanick G.J. Simon S.R. Findsen E.W. Ondrias M.R. Macdonald V.W. Localized control of ligand binding in hemoglobin: Effect of tertiary structure on picosecond geminate recombination.Science. 1985; 229: 187-190Crossref PubMed Scopus (0) Google Scholar), where linkages were shown to exist in the related protein hemoglobin, between the protein conformations and events at the iron atom and the heme group. Vibrational (infrared) spectroscopy has been particularly useful for showing the interplay between conformational dynamics and function in myoglobin. Because of its triple bond, the stretching frequency of CO is shifted to a region not complicated by other signals. The CO then becomes a sensitive monitor of properties of the surrounding protein. In a series of studies, Nienhaus and coworkers observed the effect of the protein and its different effects on CO, including states shortly after it is unbound from the iron atom, and when trapped in preformed cavities inside the protein matrix (15Nienhaus K. Deng P. Kriegl J.M. Nienhaus G.U. Structural dynamics of myoglobin: Effect of internal cavities on ligand migration and binding.Biochemistry. 2003; 42: 9647-9658Crossref PubMed Scopus (0) Google Scholar, 16Ostermann A. Waschipky R. Parak F.G. Nienhaus G.U. Ligand binding and conformational motions in myoglobin.Nature. 2000; 404: 205-208Crossref PubMed Scopus (354) Google Scholar). Myoglobin was also shown to “relax” to a new conformation after photolysis that affects the kinetics of its rebinding (17Nienhaus G.U. Mourant J.R. Frauenfelder H. Spectroscopic evidence for conformational relaxation in myoglobin.Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2902-2906Crossref PubMed Google Scholar). Furthermore, mutagenesis has been extensively used to perturb the structure and dynamics of myoglobin and test models of its dynamic behavior (18Carlson M.L. Regan R. Elber R. Li H. Phillips Jr., G.N. Olson J.S. Gibson Q.H. Nitric oxide recombination to double mutants of myoglobin: Role of ligand diffusion in a fluctuating heme pocket.Biochemistry. 1994; 33: 10597-10606Crossref PubMed Google Scholar, 19Quillin M.L. Arduini R.M. Olson J.S. Phillips Jr., G.N. High-resolution crystal structures of distal histidine mutants of sperm whale myoglobin.J. Mol. Biol. 1993; 234: 140-155Crossref PubMed Google Scholar, 20Gibson Q.H. Regan R. Elber R. Olson J.S. Carver T.E. Distal pocket residues affect picosecond ligand recombination in myoglobin. An experimental and molecular dynamics study of position 29 mutants.J. Biol. Chem. 1992; 267: 22022-22034Abstract Full Text PDF PubMed Google Scholar). In one study the stretching frequencies of the CO and the iron-C bonds were correlated with oxygen and CO binding affinities through an electrostatic process (21Phillips G.N. Teodoro M.L. Li T. Smith B. Olson J.S. Bound CO is a molecular probe of electrostatic potential in the distal pocket of myoglobin.J. Phys. Chem. B. 1999; 103: 8817-8829Crossref Google Scholar). And other studies probed the need for dynamic components of ligand entry and escape including removal of the distal histidine gate (19Quillin M.L. Arduini R.M. Olson J.S. Phillips Jr., G.N. High-resolution crystal structures of distal histidine mutants of sperm whale myoglobin.J. Mol. Biol. 1993; 234: 140-155Crossref PubMed Google Scholar), or opening the gate with lowered pH (22Yang F. Phillips Jr., G.N. Crystal structures of CO−, Deoxy- and Met-myoglobins at various pH values.J. Mol. Biol. 1996; 256: 762-774Crossref PubMed Scopus (0) Google Scholar) or propping the gate open with a bound ligand, not unlike leaving a trail as in Ariadne’s thread (23Johnson K.A. Olson J.S. Phillips Jr., G.N. Structure of myoglobin-ethyl isocyanide. Histidine as a swinging door for ligand entry.J. Mol. Biol. 1989; 207: 459-463Crossref PubMed Google Scholar). Taken together, these results suggest that not only chemical bond formation and electrostatics (24Nienhaus K. Ostermann A. Nienhaus G.U. Parak F.G. Schmidt M. Ligand migration and protein fluctuations in myoglobin mutant L29W.Biochemistry. 2005; 44: 5095-5105Crossref PubMed Scopus (0) Google Scholar) but also transient passageways within the protein matrix are determinates of the rates of rebinding of the iron to (or release from) the protein. These transient kinetic processes may serve as some sort of kinetic proofreading that supports more preferential binding of oxygen (21Phillips G.N. Teodoro M.L. Li T. Smith B. Olson J.S. Bound CO is a molecular probe of electrostatic potential in the distal pocket of myoglobin.J. Phys. Chem. B. 1999; 103: 8817-8829Crossref Google Scholar). Looking deeper into the quantum mechanical and vibrational world of myoglobin and the biochemistry of its iron, Falahati et al. (25Falahati K. Tamura H. Burghardt I. Huix-Rotllant M. Ultrafast carbon monoxide photolysis and heme spin-crossover in myoglobin via nonadiabatic quantum dynamics.Nat. Commun. 2018; 9: 4502Crossref PubMed Scopus (14) Google Scholar) have described a dynamic process during ligand dissociation involving oscillatory dynamics of the iron in the heme during a spin transition that breaks the symmetry of the system, encourages the transfer of an electron from the porphyrin to the iron, and retards rebinding of the ligand to the iron. This same spin transition forces the movement of the iron out of the plane of the heme and is part of the description of the mechanism of cooperativity in hemoglobin (26Monod J. Wyman J. Changeux J.P. On the nature of allosteric transitions: A plausible model.J. Mol. Biol. 1965; 12: 88-118Crossref PubMed Google Scholar, 27Koshland Jr., D.E. Nemethy G. Filmer D. Comparison of experimental binding data and theoretical models in proteins containing subunits.Biochemistry. 1966; 5: 365-385Crossref PubMed Google Scholar). The overall dynamics of the entire myoglobin molecule have also been studied by a variety of methods, including X-ray crystallography, neutron scattering, and molecular dynamics (MD) simulations. Comparisons of the dynamics in different crystal forms, where the amplitudes of small harmonic displacements can be fit to the diffraction data, showed a consistent pattern of overall motions, once the crystal packing effects were taken into account (28Phillips Jr., G.N. Comparison of the dynamics of myoglobin in different crystal forms.Biophys. J. 1990; 57: 381-383Abstract Full Text PDF PubMed Google Scholar, 29Kondrashov D.A. Zhang W. Aranda R. t Stec B. Phillips Jr., G.N. Sampling of the native conformational ensemble of myoglobin via structures in different crystalline environments.Proteins. 2008; 70: 353-362Crossref PubMed Scopus (0) Google Scholar). In another study, elastic, quasi-elastic, and inelastic components of neutron scattering were measured and compared with calculations from an MD trajectory, showing good correspondence and supporting an atomic model describing atomic displacements on the 0.3- to 100-picosecond time scale (30Smith J. Kuczera K. Karplus M. Dynamics of myoglobin: Comparison of simulation results with neutron scattering spectra.Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1601-1605Crossref PubMed Google Scholar). All of the results describe a situation where some parts of the protein are more mobile, namely, the connection between the C and D helices (CD corner) and the N and C termini. The dynamics of the CD corner, particularly at position 46, allow coupled positioning of the distal histidine for hydrogen bonding to oxygen and to the opening of the histidine gate (31Lai H.H. Li T. Lyons D.S. Phillips Jr., G.N. Olson J.S. Gibson Q.H. Phe-46(CD4) orients the distal histidine for hydrogen bonding to bound ligands in sperm whale myoglobin.Proteins. 1995; 22: 322-339Crossref PubMed Scopus (48) Google Scholar). The role of the solvent in defining protein dynamics in myoglobin has also been explored to show aspects of the water dynamics (32Phillips Jr., G.N. Pettitt B.M. Structure and dynamics of the water around myoglobin.Protein Sci. 1995; 4: 149-158Crossref PubMed Scopus (0) Google Scholar) and slaving of the protein conformational transitions by the solvent (33Lubchenko V. Wolynes P.G. Frauenfelder H. Mosaic energy landscapes of liquids and the control of protein conformational dynamics by glass-forming solvents.J. Phys. Chem. B. 2005; 109: 7488-7499Crossref PubMed Scopus (61) Google Scholar). Another commonly studied model system for protein dynamics is adenylate kinase, a small enzyme that catalyzes the reversible transfer of a phosphate group from ADP and AMP to maintain an equilibrium among ADP, AMP, and ATP. The motions are dramatic, including the opening and closing of a “lid” and a “flap” that cover the ATP- and AMP-binding sites, respectively (Fig. 2). At present there are over 1200 papers with adenylate kinase in the title via PubMed. Enzymology (34Rhoads D.G. Lowenstein J.M. Initial velocity and equilibrium kinetics of myokinase.J. Biol. Chem. 1968; 243: 3963-3972Abstract Full Text PDF PubMed Google Scholar, 35Khoo J.C. Russell Jr., P.J. Adenylate kinase from bakers' yeast. IV. Substrate and inhibitor structurll requirements.J. Biol. Chem. 1970; 245: 4163-4167Abstract Full Text PDF PubMed Google Scholar), genetics (36Ferber D.M. Haney P.J. Berk H. Lynn D. Konisky J. The adenylate kinase genes of M. voltae, M. thermolithotrophicus, M. jannaschii, and M. igneus define a new family of adenylate kinases.Gene. 1997; 185: 239-244Crossref PubMed Scopus (0) Google Scholar), crystallography (37Schulz G.E. Elzinga M. Marx F. Schrimer R.H. Three dimensional structure of adenyl kinase.Nature. 1974; 250: 120-123Crossref PubMed Google Scholar, 38Criswell A.R. Bae E. Stec B. Konisky J. Phillips Jr., G.N. Structures of thermophilic and mesophilic adenylate kinases from the genus Methanococcus.J. Mol. Biol. 2003; 330: 1087-1099Crossref PubMed Scopus (53) Google Scholar, 39Berry M.B. Bae E. Bilderback T.R. Glaser M. Phillips Jr., G.N. Crystal structure of ADP/AMP complex of Escherichia coli adenylate kinase.Proteins. 2006; 62: 555-556Crossref PubMed Scopus (29) Google Scholar, 40Henzler-Wildman K.A. Thai V. Lei M. Ott M. Wolf-Watz M. Fenn T. Pozharski E. Wilson M.A. Petsko G.A. Karplus M. Hubner C.G. Kern D. Intrinsic motions along an enzymatic reaction trajectory.Nature. 2007; 450: 838-844Crossref PubMed Scopus (669) Google Scholar), solution scattering (41Daily M.D. Makowski L. Phillips Jr., G.N. Cui Q. Large-scale motions in the adenylate kinase solution ensemble: Coarse-grained simulations and comparison with solution X-ray scattering.Chem. Phys. 2012; 396: 84-91Crossref PubMed Scopus (0) Google Scholar), NMR (42Kerns S.J. Agafonov R.V. Cho Y.J. Pontiggia F. Otten R. Pachov D.V. Kutter S. Phung L.A. Murphy P.N. Thai V. Alber T. Hagan M.F. Kern D. The energy landscape of adenylate kinase during catalysis.Nat. Struct. Mol. Biol. 2015; 22: 124-131Crossref PubMed Scopus (80) Google Scholar, 43Krishnamurthy H. Munro K. Yan H. Vieille C. Dynamics in Thermotoga neapolitana adenylate kinase: 15N relaxation and hydrogen-deuterium exchange studies of a hyperthermophilic enzyme highly active at 30 degrees C.Biochemistry. 2009; 48: 2723-2739Crossref PubMed Scopus (0) Google Scholar), MD simulations (44Whitford P.C. Gosavi S. Onuchic J.N. Conformational transitions in adenylate kinase. Allosteric communication reduces misligation.J. Biol. 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Deciphering hierarchical features in the energy landscape of adenylate kinase folding/unfolding.J. Chem. Phys. 2018; 148: 123325Crossref PubMed Scopus (9) Google Scholar, 49Lin C.Y. Huang J.Y. Lo L.W. Deciphering the catalysis-associated conformational changes of human adenylate kinase 1 with single-molecule spectroscopy.J. Phys. Chem. B. 2013; 117: 13947-13955Crossref PubMed Scopus (2) Google Scholar), hydrogen exchange mass spectrometry (43Krishnamurthy H. Munro K. Yan H. Vieille C. Dynamics in Thermotoga neapolitana adenylate kinase: 15N relaxation and hydrogen-deuterium exchange studies of a hyperthermophilic enzyme highly active at 30 degrees C.Biochemistry. 2009; 48: 2723-2739Crossref PubMed Scopus (0) Google Scholar), various spectroscopies, mutagenesis (50Olsson U. Wolf-Watz M. Overlap between folding and functional energy landscapes for adenylate kinase conformational change.Nat. Commun. 2010; 1: 111Crossref PubMed Scopus (70) Google Scholar, 51Bae E. Phillips Jr., G.N. Roles of static and dynamic domains in stability and catalysis of adenylate kinase.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2132-2137Crossref PubMed Scopus (0) Google Scholar), evolution (52Miller C. Davlieva M. Wilson C. White K.I. Counago R. Wu G. Myers J.C. Wittung-Stafshede P. Shamoo Y. Experimental evolution of adenylate kinase reveals contrasting strategies toward protein thermostability.Biophys. J. 2010; 99: 887-896Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 53Lange S. Rozario C. Muller M. Primary structure of the hydrogenosomal adenylate kinase of Trichomonas vaginalis and its phylogenetic relationships.Mol. Biochem. Parasitol. 1994; 66: 297-308Crossref PubMed Scopus (0) Google Scholar), phylogeny (54Saavedra H.G. Wrabl J.O. Anderson J.A. Li J. Hilser V.J. Dynamic allostery can drive cold adaptation in enzymes.Nature. 2018; 558: 324-328Crossref PubMed Scopus (77) Google Scholar), and bioinformatics (55Schulz G.E. Schiltz E. Tomasselli A.G. Frank R. Brune M. Wittinghofer A. Schirmer R.H. Structural relationships in the adenylate kinase family.Eur. J. Biochem. 1986; 161: 127-132Crossref PubMed Scopus (0) Google Scholar), and others have all been employed to gain insight regarding the connections between structure, dynamics, and function. There is not a single model for a pathway commensurate with all the studies. Recent contributors to work on adenylate kinase make regular use energy landscape theory in their interpretations (56Wang Y. Makowski L. Fine structure of conformational ensembles in adenylate kinase.Proteins. 2018; 86: 332-343Crossref PubMed Scopus (5) Google Scholar, 57Li D. Liu M.S. Ji B. Mapping the dynamics landscape of conformational transitions in enzyme: The adenylate kinase case.Biophys. J. 2015; 109: 647-660Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 58Adkar B.V. Jana B. Bagchi B. Role of water in the enzymatic catalysis: Study of ATP + AMP--> 2ADP conversion by adenylate kinase.J. Phys. Chem. A. 2011; 115: 3691-3697Crossref PubMed Scopus (0) Google Scholar, 59Feng Y. Yang L. Kloczkowski A. Jernigan R.L. The energy profiles of atomic conformational transition intermediates of adenylate kinase.Proteins. 2009; 77: 551-558Crossref PubMed Scopus (0) Google Scholar).Figure 2The enzyme adenylate kinase undergoes large, dynamic conformational changes during its catalytic cycle. A, proposed reaction scheme for the enzyme adenylate kinase (E) including the steps of substrate binding (kon), lid closing (kclose), phosphotransfer (kp-transfer), lid opening (kopen), and substrate dissociation (koff). B, superposition of molecule A of apo Aquifex (red) with apo E. coli (blue) Adk reveals only small changes in the overall structure between the homologues, as indicated by the dashed ovals. C, superposition of apo Aquifex Adk (red) and Aquifex Adk in complex (green) with the substrate analog Zn2+.Ap5A (shown as ball and stick in gray) demonstrates the closure of the ATP and AMP lids on substrate binding. Figure from (40Henzler-Wildman K.A. Thai V. Lei M. Ott M. Wolf-Watz M. Fenn T. Pozharski E. Wilson M.A. Petsko G.A. Karplus M. Hubner C.G. Kern D. Intrinsic motions along an enzymatic reaction trajectory.Nature. 2007; 450: 838-844Crossref PubMed Scopus (669) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The protein is widely studied by structural methods. There are no fewer than 115 PDB entries with adenylate kinase in the title, representing 27 species and multiple states of the protein with and without bound ligands and metals, bound inhibitors, and occasionally ensembles of structures that represent interconverting states of the enzyme. These coordinates have been used to infer dynamic transitions (60Schotte F. Soman J. Olson J.S. Wulff M. Anfinrud P.A. Picosecond time-resolved X-ray crystallography: Probing protein function in real time.J. Struct. Biol. 2004; 147: 235-246Crossref PubMed Scopus (0) Google Scholar) and catch glimpses of intermediates (38Criswell A.R. Bae E. Stec B. Konisky J. Phillips Jr., G.N. Structures of thermophilic and mesophilic adenylate kinases from the genus Methanococcus.J. Mol. Biol. 2003; 330: 1087-1099Crossref PubMed Scopus (53) Google Scholar, 40Henzler-Wildman K.A. Thai V. Lei M. Ott M. Wolf-Watz M. Fenn T. Pozharski E. Wilson M.A. Petsko G.A. Karplus M. Hubner C.G. Kern D. Intrinsic motions along an enzymatic reaction trajectory.Nature. 2007; 450: 838-844Crossref PubMed Scopus (669) Google Scholar) and examine ensembles from NMR (61Miron S. Munier-Lehmann H. Craescu C.T. Structural and dynamic studies on ligand-free adenylate kinase from Mycobacterium tuberculosis revealed a closed conformation that can be related to the reduced catalytic activity.Biochemistry. 2004; 43: 67-77Crossref PubMed Scopus (0) Google Scholar) and crystallography (Bae and Phillips, unpublished). They have also been mapped to energy landscapes created from MD simulations (44Whitford P.C. Gosavi S. Onuchic J.N. Conformational transitions in adenylate kinase. Allosteric communication reduces misligation.J. Biol. Chem. 2008; 283: 2042-2048Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 45Daily M.D. Phillips Jr., G.N. Cui Q. Many local motions cooperate to produce the adenylat" @default.
• W3157345013 created "2021-05-10" @default.
• W3157345013 creator A5009606823 @default.
• W3157345013 creator A5018889599 @default.
• W3157345013 date "2021-01-01" @default.
• W3157345013 modified "2023-10-06" @default.
• W3157345013 title "Moving beyond static snapshots: Protein dynamics and the Protein Data Bank" @default.
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