Determination of conformationally heterogeneous states of proteins.

Although conformationally heterogeneous states of proteins are involved in a range of important biological processes, including protein folding and misfolding, and signal transduction, detailed knowledge of their structure and dynamics is still largely missing. Proteins in many of these states are constantly changing shape, such that they are better described as ensembles of conformations rather than in terms of well-defined structures, as is normally the case for native states. Methods in which molecular simulations are combined with experimental measurements are emerging as a powerful route to the accurate determination of the conformational properties of these states of proteins.

[1]  C. Dobson,et al.  Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations. , 2005, Journal of the American Chemical Society.

[2]  Rafael Brüschweiler,et al.  Identification of slow correlated motions in proteins using residual dipolar and hydrogen-bond scalar couplings. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[4]  Michele Vendruscolo,et al.  Determination of the folding transition states of barnase by using PhiI-value-restrained simulations validated by double mutant PhiIJ-values. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. R. Fresht.  Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding , 1999 .

[6]  Frans A A Mulder,et al.  Correlated dynamics of consecutive residues reveal transient and cooperative unfolding of secondary structure in proteins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Michele Vendruscolo,et al.  Towards complete descriptions of the free–energy landscapes of proteins , 2005, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

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

[9]  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.

[10]  M. Vendruscolo,et al.  Determination of protein structures consistent with NMR order parameters. , 2004, Journal of the American Chemical Society.

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

[12]  J. Pitera,et al.  Assessing the effect of conformational averaging on the measured values of observables , 2001, Journal of biomolecular NMR.

[13]  A. Fersht,et al.  Protein Folding and Unfolding at Atomic Resolution , 2002, Cell.

[14]  G. Wider,et al.  NMR determination of residual structure in a urea-denatured protein, the 434-repressor. , 1992, Science.

[15]  Kresten Lindorff-Larsen,et al.  Determination of an ensemble of structures representing the denatured state of the bovine acyl-coenzyme a binding protein. , 2004, Journal of the American Chemical Society.

[16]  M. Karplus,et al.  Exploration of partially unfolded states of human alpha-lactalbumin by molecular dynamics simulation. , 2001, Journal of molecular biology.

[17]  T. Kiefhaber,et al.  End-to-end distance distributions and intrachain diffusion constants in unfolded polypeptide chains indicate intramolecular hydrogen bond formation , 2006, Proceedings of the National Academy of Sciences.

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

[19]  A Joshua Wand,et al.  Changes in calmodulin main-chain dynamics upon ligand binding revealed by cross-correlated NMR relaxation measurements. , 2005, Journal of the American Chemical Society.

[20]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[21]  Ad Bax,et al.  An empirical backbone-backbone hydrogen-bonding potential in proteins and its applications to NMR structure refinement and validation. , 2004, Journal of the American Chemical Society.

[22]  Eilon Sherman,et al.  Coil-globule transition in the denatured state of a small protein. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Forman-Kay,et al.  Calculation of ensembles of structures representing the unfolded state of an SH3 domain. , 2001, Journal of molecular biology.

[24]  M. Blackledge,et al.  Defining long-range order and local disorder in native alpha-synuclein using residual dipolar couplings. , 2005, Journal of the American Chemical Society.

[25]  H. Dyson,et al.  Intrinsically unstructured proteins and their functions , 2005, Nature Reviews Molecular Cell Biology.

[26]  Gert Vriend,et al.  Validation of protein structures derived by NMR spectroscopy , 2004 .

[27]  D E Wemmer,et al.  Two-state allosteric behavior in a single-domain signaling protein. , 2001, Science.

[28]  R. Kaptein,et al.  Describing Partially Unfolded States of Proteins from Sparse NMR Ddata , 2005, Journal of biomolecular NMR.

[29]  M. Karplus,et al.  Protein Folding: A Perspective from Theory and Experiment , 1998 .

[30]  G. Marius Clore,et al.  Using Xplor‐NIH for NMR Molecular Structure Determination , 2006 .

[31]  C. Dobson,et al.  Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR , 2004, Nature.

[32]  Christopher M. Dobson,et al.  Exploration of partially unfolded states of human α-lactalbumin by molecular dynamics simulation , 2001 .

[33]  C. Brooks,et al.  From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding. , 2001, Annual review of physical chemistry.

[34]  M. DePristo,et al.  Relation between native ensembles and experimental structures of proteins. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Kurt Wüthrich,et al.  Internal motion in globular proteins , 1978 .

[36]  C. Griesinger,et al.  Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  S. Radford,et al.  Determination of an ensemble of structures representing the intermediate state of the bacterial immunity protein Im7. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[38]  D. Shortle,et al.  Characterization of long-range structure in the denatured state of staphylococcal nuclease. II. Distance restraints from paramagnetic relaxation and calculation of an ensemble of structures. , 1997, Journal of molecular biology.

[39]  B. L. de Groot,et al.  Probing conformational disorder in neurotensin by two-dimensional solid-state NMR and comparison to molecular dynamics simulations. , 2005, Biophysical journal.

[40]  D. Boehr,et al.  The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis , 2006, Science.

[41]  Michael R. Shirts,et al.  Native-like mean structure in the unfolded ensemble of small proteins. , 2002, Journal of molecular biology.

[42]  G. Bouvignies,et al.  Simultaneous determination of protein backbone structure and dynamics from residual dipolar couplings. , 2006, Journal of the American Chemical Society.

[43]  M. Karplus,et al.  Molecular dynamics and protein function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Rafael Brüschweiler,et al.  General framework for studying the dynamics of folded and nonfolded proteins by NMR relaxation spectroscopy and MD simulation. , 2002, Journal of the American Chemical Society.

[45]  Lewis E. Kay,et al.  New Tools Provide New Insights in NMR Studies of Protein Dynamics , 2006, Science.

[46]  K. Lindorff-Larsen,et al.  Characterization of the residual structure in the unfolded state of the Δ131Δ fragment of staphylococcal nuclease , 2006 .

[47]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[48]  M. Karplus,et al.  Structures and relative free energies of partially folded states of proteins , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Elisha Haas,et al.  The study of protein folding and dynamics by determination of intramolecular distance distributions and their fluctuations using ensemble and single-molecule FRET measurements. , 2005, Chemphyschem : a European journal of chemical physics and physical chemistry.

[50]  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.

[51]  W. Eaton,et al.  Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy , 2002, Nature.

[52]  Michele Vendruscolo,et al.  Dynamic Visions of Enzymatic Reactions , 2006, Science.

[53]  A. R. Fersht,et al.  Solution structure of a protein denatured state and folding intermediate , 2005, Nature.

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

[55]  J M Thornton,et al.  Analysis of main chain torsion angles in proteins: prediction of NMR coupling constants for native and random coil conformations. , 1996, Journal of molecular biology.

[56]  P. Wolynes,et al.  The energy landscapes and motions of proteins. , 1991, Science.