Relation between native ensembles and experimental structures of proteins.

Different experimental structures of the same protein or of proteins with high sequence similarity contain many small variations. Here we construct ensembles of "high-sequence similarity Protein Data Bank" (HSP) structures and consider the extent to which such ensembles represent the structural heterogeneity of the native state in solution. We find that different NMR measurements probing structure and dynamics of given proteins in solution, including order parameters, scalar couplings, and residual dipolar couplings, are remarkably well reproduced by their respective high-sequence similarity Protein Data Bank ensembles; moreover, we show that the effects of uncertainties in structure determination are insufficient to explain the results. These results highlight the importance of accounting for native-state protein dynamics in making comparisons with ensemble-averaged experimental data and suggest that even a modest number of structures of a protein determined under different conditions, or with small variations in sequence, capture a representative subset of the true native-state ensemble.

[1]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[2]  G. Lipari.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules , 1982 .

[3]  A. Szabó,et al.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity , 1982 .

[4]  R. Levy,et al.  Protein dynamics and NMR relaxation: comparison of simulations with experiment , 1982, Nature.

[5]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[6]  M Karplus,et al.  Molecular dynamics of myoglobin at 298 degrees K. Results from a 300-ps computer simulation. , 1985, Biophysical journal.

[7]  A. Lesk,et al.  The relation between the divergence of sequence and structure in proteins. , 1986, The EMBO journal.

[8]  D. Chandler,et al.  Introduction To Modern Statistical Mechanics , 1987 .

[9]  Axel T. Brunger,et al.  Model bias in macromolecular crystal structures , 1992 .

[10]  D. Ohlendorf,et al.  Acuracy of refined protein structures. II. Comparison of four independently refined models of human interleukin 1beta. , 1994, Acta crystallographica. Section D, Biological crystallography.

[11]  A. Brünger,et al.  Conformational variability of solution nuclear magnetic resonance structures. , 1995, Journal of molecular biology.

[12]  B. Matthews,et al.  Protein flexibility and adaptability seen in 25 crystal forms of T4 lysozyme. , 1995, Journal of molecular biology.

[13]  P E Bourne,et al.  Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. , 1998, Protein engineering.

[14]  L. Kay,et al.  Correlation between binding and dynamics at SH2 domain interfaces , 1998, Nature Structural Biology.

[15]  Ad Bax,et al.  Validation of Protein Structure from Anisotropic Carbonyl Chemical Shifts in a Dilute Liquid Crystalline Phase , 1998 .

[16]  M Paoli,et al.  The stereochemical mechanism of the cooperative effects in hemoglobin revisited. , 1998, Annual review of biophysics and biomolecular structure.

[17]  M. Karplus,et al.  Effective energy function for proteins in solution , 1999, Proteins.

[18]  L. Kay,et al.  Analysis of deuterium relaxation-derived methyl axis order parameters and correlation with local structure , 1999, Journal of biomolecular NMR.

[19]  J. Andrew McCammon,et al.  Method for Including the Dynamic Fluctuations of a Protein in Computer-Aided Drug Design , 1999 .

[20]  Matthias Buck,et al.  Internal and Overall Peptide Group Motion in Proteins: Molecular Dynamics Simulations for Lysozyme Compared with Results from X-ray and NMR Spectroscopy , 1999 .

[21]  P E Bourne,et al.  The Protein Data Bank. , 2002, Nucleic acids research.

[22]  F. Bushman,et al.  Developing a dynamic pharmacophore model for HIV-1 integrase. , 2000, Journal of medicinal chemistry.

[23]  A. Joshua Wand,et al.  Dynamic activation of protein function: A view emerging from NMR spectroscopy , 2001, Nature Structural Biology.

[24]  J Meiler,et al.  Model-free approach to the dynamic interpretation of residual dipolar couplings in globular proteins. , 2001, Journal of the American Chemical Society.

[25]  C. Dobson,et al.  A refined solution structure of hen lysozyme determined using residual dipolar coupling data , 2001, Protein science : a publication of the Protein Society.

[26]  A. Bax,et al.  Dipolar couplings in macromolecular structure determination. , 2001, Methods in enzymology.

[27]  J. Berg,et al.  Molecular dynamics simulations of biomolecules , 2002, Nature Structural Biology.

[28]  M Karplus,et al.  Relation between sequence and structure of HIV-1 protease inhibitor complexes: a model system for the analysis of protein flexibility. , 2002, Journal of molecular biology.

[29]  H. Wolfson,et al.  Access the most recent version at doi: 10.1110/ps.21302 References , 2001 .

[30]  B. Halle,et al.  Flexibility and packing in proteins , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Rafael Brüschweiler,et al.  Contact model for the prediction of NMR N-H order parameters in globular proteins. , 2002, Journal of the American Chemical Society.

[32]  Lorna J. Smith,et al.  Long-Range Interactions Within a Nonnative Protein , 2002, Science.

[33]  Ad Bax,et al.  Insights into the mobility of methyl-bearing side chains in proteins from (3)J(CC) and (3)J(CN) couplings. , 2003, Journal of the American Chemical Society.

[34]  Dynamics and entropy of a calmodulin-peptide complex studied by NMR and molecular dynamics. , 2003, Biochemistry.

[35]  S. Homans,et al.  Methyl side-chain dynamics in proteins using selective enrichment with a single isotopomer. , 2003, Journal of the American Chemical Society.

[36]  Ad Bax,et al.  Quaternary structure of hemoglobin in solution , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  L. Kay,et al.  Correlation between 2H NMR side-chain order parameters and sequence conservation in globular proteins. , 2003, Journal of the American Chemical Society.

[38]  A. Palmer,et al.  NMR characterization of the dynamics of biomacromolecules. , 2004, Chemical reviews.

[39]  J. Prestegard,et al.  Residual dipolar couplings in structure determination of biomolecules. , 2004, Chemical reviews.

[40]  G. Clore,et al.  How much backbone motion in ubiquitin is required to account for dipolar coupling data measured in multiple alignment media as assessed by independent cross-validation? , 2004, Journal of the American Chemical Society.

[41]  G. Marius Clore,et al.  Amplitudes of Protein Backbone Dynamics and Correlated Motions in a Small α/β Protein: Correspondence of Dipolar Coupling and Heteronuclear Relaxation Measurements† , 2004 .

[42]  M. DePristo,et al.  Heterogeneity and inaccuracy in protein structures solved by X-ray crystallography. , 2004, Structure.

[43]  Hydrophobic core fluidity of homologous protein domains: relation of side-chain dynamics to core composition and packing. , 2004, Biochemistry.

[44]  L. Kay,et al.  The response of internal dynamics to hydrophobic core mutations in the SH3 domain from the Fyn tyrosine kinase , 2004, Protein science : a publication of the Protein Society.

[45]  Andrew L. Lee,et al.  Long-range dynamic effects of point mutations propagate through side chains in the serine protease inhibitor eglin c. , 2004, Biochemistry.

[46]  Rafael Brüschweiler,et al.  Prediction of methyl-side Chain Dynamics in Proteins , 2004, Journal of biomolecular NMR.

[47]  M. Karplus,et al.  The origin of protein sidechain order parameter distributions. , 2004, Journal of the American Chemical Society.

[48]  L. Kay,et al.  NMR studies of protein structure and dynamics. , 2005, Journal of magnetic resonance.

[49]  Jane Clarke,et al.  What contributions to protein side-chain dynamics are probed by NMR experiments? A molecular dynamics simulation analysis. , 2005, Journal of molecular biology.

[50]  K. Lindorff-Larsen,et al.  Interpreting Dynamically-Averaged Scalar Couplings in Proteins , 2005, Journal of biomolecular NMR.

[51]  M. DePristo,et al.  Simultaneous determination of protein structure and dynamics , 2005, Nature.

[52]  L. Kay,et al.  Intrinsic dynamics of an enzyme underlies catalysis , 2005, Nature.

[53]  G. Clore,et al.  Concordance of residual dipolar couplings, backbone order parameters and crystallographic B-factors for a small alpha/beta protein: a unified picture of high probability, fast atomic motions in proteins. , 2006, Journal of molecular biology.