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Investigation of Protein Folding by Coarse-Grained Molecular Dynamics with the UNRES Force Field
| Content Provider | Scilit |
|---|---|
| Author | Maisuradze, Gia G. Senet, Patrick Czaplewski, Cezary Liwo, Adam Scheraga, Harold A. |
| Copyright Year | 2010 |
| Abstract | Coarse-grained molecular dynamics simulations offer a dramatic extension of the time-scale of simulations compared to all-atom approaches. In this article, we describe the use of the physics-based united-residue (UNRES) force field, developed in our laboratory, in protein-structure simulations. We demonstrate that this force field offers about a 4000-times extension of the simulation time scale; this feature arises both from averaging out the fast-moving degrees of freedom and reduction of the cost of energy and force calculations compared to all-atom approaches with explicit solvent. With massively parallel computers, microsecond folding simulation times of proteins containing about 1000 residues can be obtained in days. A straightforward application of canonical UNRES/MD simulations, demonstrated with the example of the N-terminal part of the B-domain of staphylococcal protein A (PDB code: 1BDD, a three-α-helix bundle), discerns the folding mechanism and determines kinetic parameters by parallel simulations of several hundred or more trajectories. Use of generalized-ensemble techniques, of which the multiplexed replica exchange method proved to be the most effective, enables us to compute thermodynamics of folding and carry out fully physics-based prediction of protein structure, in which the predicted structure is determined as a mean over the most populated ensemble below the folding-transition temperature. By using principal component analysis of the UNRES folding trajectories of the formin-binding protein WW domain (PDB code: 1E0L; a three-stranded antiparallel β-sheet) and 1BDD, we identified representative structures along the folding pathways and demonstrated that only a few (low-indexed) principal components can capture the main structural features of a protein-folding trajectory; the potentials of mean force calculated along these essential modes exhibit multiple minima, as opposed to those along the remaining modes that are unimodal. In addition, a comparison between the structures that are representative of the minima in the free-energy profile along the essential collective coordinates of protein folding (computed by principal component analysis) and the free-energy profile projected along the virtual-bond dihedral angles γ of the backbone revealed the key residues involved in the transitions between the different basins of the folding free-energy profile, in agreement with existing experimental data for 1E0L. |
| Related Links | http://europepmc.org/articles/pmc2849147?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849147/pdf |
| Ending Page | 4485 |
| Page Count | 15 |
| Starting Page | 4471 |
| ISSN | 10895639 |
| e-ISSN | 15205215 |
| DOI | 10.1021/jp9117776 |
| Journal | The Journal of Physical Chemistry A |
| Issue Number | 13 |
| Volume Number | 114 |
| Language | English |
| Publisher | American Chemical Society (ACS) |
| Publisher Date | 2010-02-18 |
| Access Restriction | Open |
| Subject Keyword | Journal: The Journal of Physical Chemistry A Molecular Dynamics Unres Force Field Generalized-ensemble Methods Principal-component Analysis Free Energy Landscape |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Physical and Theoretical Chemistry |
