TCB Publications - Abstract

Wei Han and Klaus Schulten. Further optimization of a hybrid united-atom and coarse-grained force field for folding simulations: Improved backbone hydration and interactions between charged side chains. Journal of Chemical Theory and Computation, 8:4413-4424, 2012. (PMC: 3507460)

HAN2012 PACE, a hybrid force field which couples united-atom protein models with coarse-grained (CG) solvent (JCTC, 2010, 6, 3373), has been further optimized, aiming to improve its efficiency for folding simulations. Backbone hydration parameters have been re-optimized based on hydration free energies of polyalanyl peptides through atomistic simulations. Also, atomistic partial charges from all-atom force fields were combined with PACE in order to provide a more realistic description of interactions between charged groups. Using replica exchange molecular dynamics (REMD), 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 NMR NOE constraints, were also well reproduced. Moreover, a systematic comparison of folding kinetics at room temperature has been made with experiments, through standard MD simulations, showing that the new PACE may speed up the actual folding kinetics 5-10 times. Together with the computational speedup benefited from coarse-graining, the force field provides opportunities to study folding mechanisms. In particular, we used the new PACE to fold a 73-residue protein, $\alpha$3D, in multiple 10-30 microsecond simulations, to its native states (C$\alpha$ RMSD $\sim$0.34 nm). Our results suggest the potential applicability of the new PACE for the study of folding and dynamics of proteins.

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