The influence of different treatments of electrostatic interactions on the thermodynamics of folding of peptides.

Replica exchange molecular dynamics simulations were performed to investigate the effects of different electrostatic treatments on the structure and thermodynamics of a small beta-hairpin forming peptide. Three different electrostatic schemes were considered: regular cutoffs, generalized reaction field (GRF), and particle mesh Ewald (PME), with the peptide modeled using OPLS/AA all-atom force field with explicit TIP3P water. Both the GRF and PME methods yielded results consistent with experiment, with free energy surfaces displaying a single minimum corresponding to the native beta-hairpin structure. In contrast, use of straight cutoffs led to the population of an additional local minimum corresponding to nonhairpin conformations that compete with the formation of the native beta-hairpin at low temperatures. This extra minimum would not be apparent in conventional constant-temperature molecular dynamics simulations run for a few nanoseconds. This result points to the critical need of careful sampling of conformational space to assess the quality of different numerical treatments of long-range forces. While differences emerged in the nature of the unfolded states populated using PME and GRF approaches, simulations on the beta-hairpin forming peptide and on two additional control peptides indicate that the GRF treatment of electrostatics offers a satisfactory compromise between accuracy and computational speed for the identification of low-energy conformations. A GRF-based approach emerges as a viable means for treating larger biological systems that would be prohibitively costly to simulate using PME methods.