Further optimization of a hybrid united-atom and coarse-grained force field for folding simulations: Improved backbone hydration and interactions between charged side chains

PACE, a hybrid force field that couples united-atom protein models with coarse-grained (CG) solvent (J. Chem. Theory Comput.2010, 6, 3373), has been further optimized, aiming to improve its efficiency for folding simulations. Backbone hydration parameters have been reoptimized based on hydration free energies of polyalanyl peptides through atomistic simulations. Also, atomistic partial charges from all-atom force fields were combined with PACE to provide a more realistic description of interactions between charged groups. Using replica exchange molecular dynamics, ab initio folding using the new PACE has been achieved for seven small proteins (16-23 residues) with different structural motifs. Experimental data about folded states, such as their stability at room temperature, melting point, and nuclear magnetic resonance nuclear Overhauser effect constraints, were also well reproduced. Moreover, a systematic comparison of folding kinetics at room temperature has been made with experiments, through standard molecular dynamics simulations, showing that the new PACE may accelerate the actual folding kinetics 5-10-fold, permitting now the study of folding mechanisms. In particular, we used the new PACE to fold a 73-residue protein, α3D, in multiple 10-30 μs simulations, to its native states (C _α root-mean-square deviation of ∼0.34 nm). Our results suggest the potential applicability of the new PACE for the study of folding and dynamics of proteins.