Development of Physics-Based Energy Functions that Predict Medium-Resolution Structures for Proteins of the #alpha#, #beta#, and #alpha#/#beta# Structural Classes

摘要

The development of three physics-based energy functions (force fields), designed to simulate the restricted free energy of proteins of the #alpha#, #beta#, and #alpha#/#beta# structural classes, is described. Each force field corresponds to a particular weighting of the united-residue (UNRES) interactions defined in earlier work.~(1-6) To find the optimal weights for the #alpha#, #beta#, and #alpha#/#beta# force fields, both the Z-score and energy gap of the native versus nonnative structures are minimized simultaneously for four benchmark proteins: 1 pou (for the #alpha# force field), 1tpm (for the #beta# force field), and 1 bdd and betanova (for the #alpha#/#beta# force field). The simultaneous minimization was carried out by using a novel Monte Carlo method, Vector Monte Carlo (VMC). For #alpha#-helical proteins, another weighting of the UNRES interactions (denoted as the #alpha#_O force field) was developed; this fourth force field is described in a companion publication (Lee, J. et at. J. Phys. Chem. B 2001, 105, 7291). The structural implications of the final weights of the four force fields, i.e., the relative contributions of the various UNRES interactions to stabilizing common structural motifs of proteins, are analyzed. The #alpha#_O, #alpha#, #beta#, and #alpha#/#beta# force fields were used inthe CASP4 exercise for ab initio protein-structure prediction with reasonable success. Finally, using a simple model system it was shown that the VMC protocol does not require exhaustive sampling of medium- and high-energy structures in order to optimize the parameters of the potential energy adequately.