This Article Full Text Full Text (PDF) All Versions of this Article: biophysj.108.133587v1 95/5/2434    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Arnautova, Y. A. Articles by Scheraga, H. A. PubMed PubMed Citation Articles by Arnautova, Y. A. Articles by Scheraga, H. A.

Use of Decoys to Optimize an All-Atom Force Field Including Hydration

Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York

Correspondence: Address reprint requests to Harold A. Scheraga, Dept. of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301. Tel.: 607-255 4034; E-mail: has5{at}cornell.edu.

A novel method of parameter optimization is proposed. It makes use of large sets of decoys generated for six nonhomologous proteins with different architecture. Parameter optimization is achieved by creating a free energy gap between sets of nativelike and nonnative conformations. The method is applied to optimize the parameters of a physics-based scoring function consisting of the all-atom ECEPP05 force field coupled with an implicit solvent model (a solvent-accessible surface area model). The optimized force field is able to discriminate near-native from nonnative conformations of the six training proteins when used either for local energy minimization or for short Monte Carlo simulated annealing runs after local energy minimization. The resulting force field is validated with an independent set of six nonhomologous proteins, and appears to be transferable to proteins not included in the optimization; i.e., for five out of the six test proteins, decoys with 1.7- to 4.0-Å all-heavy-atom root mean-square deviations emerge as those with the lowest energy. In addition, we examined the set of misfolded structures created by Park and Levitt using a four-state reduced model. The results from these additional calculations confirm the good discriminative ability of the optimized force field obtained with our decoy sets.