Application of statistical potentials to protein structure refinement from low resolution ab initio models

Recently ab initio protein structure prediction methods have advanced sufficiently so that they often assemble the correct low resolution structure of the protein. To enhance the speed of conformational search, many ab initio prediction programs adopt a reduced protein representation. However, for drug design purposes, better quality structures are probably needed. To achieve this refinement, it is natural to use a more detailed heavy atom representation. Here, as opposed to costly implicit or explicit solvent molecular dynamics simulations, knowledge‐based heavy atom pair potentials were employed. By way of illustration, we tried to improve the quality of the predicted structures obtained from the ab initio prediction program TOUCHSTONE by three methods: local constraint refinement, reduced predicted tertiary contact refinement, and statistical pair potential guided molecular dynamics. Sixty‐seven predicted structures from 30 small proteins (less than 150 residues in length) representing different structural classes (α, β, α˜/β) were examined. In 33 cases, the root mean square deviation (RMSD) from native structures improved by more than 0.3 Å; in 19 cases, the improvement was more than 0.5 Å, and sometimes as large as 1 Å. In only seven (four) cases did the refinement procedure increase the RMSD by more than 0.3 (0.5) Å. For the remaining structures, the refinement procedures changed the structures by less than 0.3 Å. While modest, the performance of the current refinement methods is better than the published refinement results obtained using standard molecular dynamics. © 2003 Wiley Periodicals, Inc. Biopolymers 70: 575–584, 2003