Recent advances in implicit solvent-based methods for biomolecular simulations

Abstract

Implicit solvent-based methods play an increasingly important role in molecular modeling of biomolecular structure and dynamics. Recent methodological developments have mainly focused on the extension of the generalized Born (GB) formalism for variable dielectric environments and accurate treatment of nonpolar solvation. Extensive efforts in parameterization of GB models and implicit solvent force fields have enabled ab initio simulation of protein folding to native or near-native structures. Another exciting area that has benefited from the advances in implicit solvent models is the development of constant pH molecular dynamics methods, which have recently been applied to the calculations of protein pK(a) values and the studies of pH-dependent peptide and protein folding.

Figure 1

Representative folded structures of trpzip2 beta hairpin (top) and Trp-cage mini-protein (bottom), in comparison with the corresponding NMR structures. Both folded structures correspond to the average structures of the largest ensembles at 270 K sampled during the last 10 nanoseconds of replica-exchange folding simulations [15]. RMSD values shown were computed using all backbone heavy atoms.

Figure 2

Representative conformations of the β amyloid peptide (10-42) under different pH conditions. The conformations were obtained as centroids of the most populated clusters from the replica-exchange CPHMD folding simulations [65]. The N-terminal residues 10-28 are shown in blue; the C-terminal residues 29-42 are shown in red. In the most aggregation-prone state (pH 6), the side chains of the central hydrophobic cluster Leu-17, Val-18, Phe-19, Phe-20 and Ala-21 are shown as van der Waals spheres in pink, grey, cyan, purple and green, respectively.