| Non-natural peptides, i.e., oligomers of beta- or of alpha- and beta-amino acid residues, have attracted considerable interest due to their potential in biomedical and materials applications. To better understand the connection between the sequence, structure and material properties of these non-natural peptides, a hierarchical protocol including hybrid quantum mechanical/classical mechanical (QM/MM) and classical molecular mechanics (MM) simulations is employed.;SCC-DFTB is an efficient QM method for the energetic and structural description of non- natural peptides. Using SCC-DFTB/MM simulation as a reference, all-atom molecular mechanical models for both cyclic and acyclic beta-amino acids are developed using an multi- objective evolutionary algorithm(MOEA). The new models are optimized in the framework of the CHARMM22 all-atom force field and are compatible with the CHARMM model for solvent, lipids and natural amino acids. They are able to reproduce correct secondary structures of some non-natural oligomers and available experimental structural data(i.e. NOE data, 3J coupling constants). The importance of careful optimization and benchmark for MM model of non-natural peptides is also highlighted by the fact that the parameters of alpha-amino acids do not transfer easily to beta-amino acids.;As initial applications, the structure and property relation of non-natural peptides is analyzed with the new MM models using generalized Born implicit solvent model. Segregation of hydrophobic and cationic groups occur easily at the membrane/solution interface for random copolymer consisting of beta-amino acids, which confirms 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. Sequence dependence of self-assembly and antimicrobial property of four 14-helical sequences is analyzed from both structural and thermodynamical points of view. The order of binding free energy of all sequences to lipid bilayer is consistent with the trends observed in antimicrobial property. For self-assembly property, the sequence dependence is not clear at two peptide level and multi-body effect should be considered. |
