Refining homology models by combining replica-exchange molecular dynamics and statistical potentials

Zhu, J., Fan, H., Periole, X., Honig, B. and Mark, A.E. (2008) Refining homology models by combining replica-exchange molecular dynamics and statistical potentials. Proteins Structure Function Bioinformatics, 72 72: 1171-1188. doi:10.1002/prot.22005


Author Zhu, J.
Fan, H.
Periole, X.
Honig, B.
Mark, A.E.
Title Refining homology models by combining replica-exchange molecular dynamics and statistical potentials
Journal name Proteins Structure Function Bioinformatics   Check publisher's open access policy
ISSN 0887-3585
Publication date 2008-03-12
Year available 2008
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1002/prot.22005
Open Access Status DOI
Volume 72
Issue 72
Start page 1171
End page 1188
Total pages 18
Place of publication United States
Publisher John Wiley & Sons, Inc
Language eng
Subject C1
060112 Structural Biology (incl. Macromolecular Modelling)
970103 Expanding Knowledge in the Chemical Sciences
Abstract A protocol is presented for the global refinement of homology models of proteins. It combines the advantages of temperature-based replica-exchange molecular dynamics (REMD) for conformational sampling and the use of statistical potentials for model selection. The protocol was tested using 21 models. Of these 14 were models of 10 small proteins for which high-resolution crystal structures were available, the remainder were targets of the recent CASPR exercise. It was found that REMD in combination with currently available force fields could sample near-native conformational states starting from high-quality homology models. Conformations in which the backbone RMSD of secondary structure elements (SSE-RMSD) was lower than the starting value by 0.5-1.0 angstrom were found for 15 out of the 21 cases (average 0.82 angstrom). Furthermore, when a simple scoring function consisting of two statistical potentials was used to rank the structures, one or more structures with SSE-RMSD of at least 0.2 angstrom lower than the starting valise was found among the five best ranked structures in 11 out of the 21 cases. The average improvement in SSE-RMSD for the best models was 0.42 angstrom. However, none of the scoring functions tested identified the structures with the lowest SSE-RMSD as the best models although all identified the native conformation as the one with lowest energy. This suggests that while the proposed protocol proved effective for the refinement of high-quality models of small proteins scoring functions remain one of the major limiting factors in structure refinement. This and other aspects by which the methodology could be further improved are discussed.
Keyword homology modeling
protein structure prediction
replica-exchange molecular dynamics
statistical potential
structure refinement
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID GM30518
TOP700.53_309
FF0455865
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: 2009 Higher Education Research Data Collection
School of Chemistry and Molecular Biosciences
 
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Created: Wed, 25 Mar 2009, 01:29:46 EST by Jennifer Falknau on behalf of School of Chemistry & Molecular Biosciences