title: Assessment of Detection and Refinement Strategies for de novo Protein Structures Using Force Field and Statistical Potentials.
abstract: De novo predictions of protein structures at high resolution are plagued by the problem of detecting the native conformation from false energy minima. In this work, we provide an assessment of various detection and refinement protocols on a small subset of the second-generation all-atom Rosetta decoy set (Tsai et al. Proteins 2003, 53, 76-87) using two potentials:  the all-atom CHARMM PARAM22 force field combined with generalized Born/surface-area (GB-SA) implicit solvation and the DFIRE-AA statistical potential. Detection schemes included DFIRE-AA conformational scoring and energy minimization followed by scoring with both GB-SA and DFIRE-AA potentials. Refinement methods included short-time (1-ps) molecular dynamics simulations, temperature-based replica exchange molecular dynamics, and a new computational unfold/refold procedure. Refinement methods include temperature-based replica exchange molecular dynamics and a new computational unfold/refold procedure. Our results indicate that simple detection with only minimization is the best protocol for finding the most nativelike structures in the decoy set. The refinement techniques that we tested are generally unsuccessful in improving detection; however, they provide marginal improvements to some of the decoy structures. Future directions in the development of refinement techniques are discussed in the context of the limitations of the protocols evaluated in this study.
authors.affiliation: Computational and Information Sciences Directorate, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, and Department of Cell Biology and Biochemistry, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Computational and Information Sciences Directorate, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, and Department of Cell Biology and Biochemistry, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Olson