Atomic-Level Characterization of the Structural Dynamics of Proteins
Following Folding Fast
Many protein functions involve conformational changes that occur on time-scales between tens of microseconds and milliseconds. This has limited the usefulness of all-atom molecular dynamics simulations, which are performed over shorter time-scales. Shaw et al. (p. 341) now report millisecond-scale, all-atom molecular dynamics simulations in an explicitly represented solvent environment. Simulation of the folding of a WW domain showed a well-defined folding pathway and simulation of the dynamics of bovine pancreatic trypsin inhibitor showed interconversion between distinct conformational states.
Abstract
Molecular dynamics (MD) simulations are widely used to study protein motions at an atomic level of detail, but they have been limited to time scales shorter than those of many biologically critical conformational changes. We examined two fundamental processes in protein dynamics—protein folding and conformational change within the folded state—by means of extremely long all-atom MD simulations conducted on a special-purpose machine. Equilibrium simulations of a WW protein domain captured multiple folding and unfolding events that consistently follow a well-defined folding pathway; separate simulations of the protein’s constituent substructures shed light on possible determinants of this pathway. A 1-millisecond simulation of the folded protein BPTI reveals a small number of structurally distinct conformational states whose reversible interconversion is slower than local relaxations within those states by a factor of more than 1000.
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Supplementary Material
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Published In
Science
Volume 330 | Issue 6002
15 October 2010
15 October 2010
Copyright
Copyright © 2010, American Association for the Advancement of Science.
Submission history
Received: 22 January 2010
Accepted: 31 August 2010
Published in print: 15 October 2010
Acknowledgments
We are very grateful to all members of the Anton hardware and software teams, without whom this work would not have been possible. We thank G. Hummer for providing us with the software to calculate position-dependent diffusion constants, A. Pan for helpful suggestions, T. Tu for assisting with trajectory analysis, A. Philippsen for helping with the BPTI renderings, K. Mackenzie for monitoring and supporting the BPTI simulation, and R. Kastleman and J. McGrady for editorial assistance.
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