Can molecular dynamics simulations provide high-resolution refinement of protein structure?
Article first published online: 20 MAR 2007
Copyright © 2007 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 67, Issue 4, pages 922–930, June 2007
How to Cite
Chen, J. and Brooks, C. L. (2007), Can molecular dynamics simulations provide high-resolution refinement of protein structure?. Proteins, 67: 922–930. doi: 10.1002/prot.21345
- Issue published online: 1 MAY 2007
- Article first published online: 20 MAR 2007
- Manuscript Accepted: 16 NOV 2006
- Manuscript Revised: 14 NOV 2006
- Manuscript Received: 18 JUL 2006
- National Institute of Health. Grant Number: RR12255
- continuum electrostatics;
- generalized Born;
- replica exchange;
- structure prediction
Recent advances in efficient and accurate treatment of solvent with the generalized Born approximation (GB) have made it possible to substantially refine the protein structures generated by various prediction tools through detailed molecular dynamics simulations. As demonstrated in a recent CASPR experiment, improvement can be quite reliably achieved when the initial models are sufficiently close to the native basin (e.g., 3–4 Å Cα RMSD). A key element to effective refinement is to incorporate reliable structural information into the simulation protocol. Without intimate knowledge of the target and prediction protocol used to generate the initial structural models, it can be assumed that the regular secondary structure elements (helices and strands) and overall fold topology are largely correct to start with, such that the protocol limits itself to the scope of refinement and focuses the sampling in vicinity of the initial structure. The secondary structures can be enforced by dihedral restraints and the topology through structural contacts, implemented as either multiple pair-wise Cα distance restraints or a single sidechain distance matrix restraint. The restraints are weakly imposed with flat-bottom potentials to allow sufficient flexibility for structural rearrangement. Refinement is further facilitated by enhanced sampling of advanced techniques such as the replica exchange method (REX). In general, for single domain proteins of small to medium sizes, 3–5 nanoseconds of REX/GB refinement simulations appear to be sufficient for reasonable convergence. Clustering of the resulting structural ensembles can yield refined models over 1.0 Å closer to the native structure in Cα RMSD. Substantial improvement of sidechain contacts and rotamer states can also be achieved in most cases. Additional improvement is possible with longer sampling and knowledge of the robust structural features in the initial models for a given prediction protocol. Nevertheless, limitations still exist in sampling as well as force field accuracy, manifested as difficulty in refinement of long and flexible loops. Proteins 2007. © 2007 Wiley-Liss, Inc.