Development of physics-based energy functions that predict medium-resolution structures for proteins of the alpha,beta and alpha/beta structural classes

The development of three physics-based energy functions (force fields), des igned to simulate the restricted free energy of proteins of the alpha, beta , and alpha/beta structural classes. is described. Each force field corresp onds to a particular weighting of the united-residue (UNRES) interactions d efined in earlier work.(1-6) To find the optimal weights for the alpha, bet a, and alpha/beta force fields. both the Z-score and energy gap of the nati ve versus normative structures are minimized simultaneously for four benchm ark proteins: 1pou for the (alpha force field), 1tpm (for the beta force fi eld), and 1bdd and betanova (for the alpha/beta force field). The simultane ous minimization was carried out by using a novel Monte Carlo method, Vecto r Monte Carlo (VMC). For alpha -helical proteins, another weighting of the UNRES interactions (denoted as the ao force field) was developed; this four th force field is described in a companion publication (Lee, J. et al. J. P hys. Chem. B 2001, 105, 7291). The structural implications of the final wei ghts of the four force fields, i.e., the relative contributions of the vari ous UNRES interactions to stabilizing common structural motifs of proteins, are analyzed. The alpha (0), alpha, beta, and alpha/beta force fields were used in the CASP4 exercise for ab initio protein -structure prediction wit h reasonable success. Finally, using a simple model system it was shown tha t the VMC protocol does not require exhaustive sampling of medium- and high -energy structures in order to optimize the parameters of the potential ene rgy adequately.