Establishing Effective Simulation Protocols for beta- and alpha/beta-Peptides. III. Molecular Mechanical Model for Acyclic beta-Amino Acids

All-atom molecular mechanics (MM) force field parameters are developed for the backbone of acyclic beta-amino acid using an improved version of the multiobjective evolutionary algorithm (MOEA). The MM model is benchmarked using beta(3)-homo-Alanine (beta(3)-hAla) diamide in water with SCC-DFTB/MM simulations as the reference. Satisfactory agreements are found between the MM and SCC-DFTB/MM results regarding the distribution of key dihedral angles for the beta(3)-hAla diamide in water. The MM model is further applied to a beta-hepta-peptide in methanol solution. The calculated NOE values and (3)J coupling constants averaged over different trajectories are consistent with experimental data. By contrast, simulations using parameters directly transferred from the CHARMM22 force field for proteins lead to much worse agreement, which highlights the importance of careful parameterization for non-natural peptides, for which the improved MOEA is particularly useful. Finally. as an initial application of the new force field parameters, the behaviors of a short random copolymer consisting of beta amino acids in bulk solution and membrane/water interface are studied using a generalized Born implicit solvent model (GBSW). Results for four selected sequences show that segregation of hydrophobic and cationic groups occur easily at the membrane/solution interface for all sequences. The sequence that features alternating short blocks exhibits signs of lower stability at the interface compared to other sequences. These results confirm the hypothesis in recent experimental studies that beta-amino-acid based random copolymers can develop a high degree of amphiphilicity without regular three-dimensional structure. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 31: 2063-2077, 2010