Application of a Distance-Dependent Sigmoidal Dielectric Constant to the REMC/SAAP3D Simulations of Chignolin, Trp-Cage, and the G10q Mutant.

The replica-exchange Monte Carlo method based on the single amino acid potential (SAAP) force field, i.e., REMC/SAAP3D, was recently developed by our group for the molecular simulation of short peptides. In this study, the method has been improved by applying a distance-dependent dielectric (DDD) constant and extended to the peptides containing D-amino acid (AA) residues. For chignolin (10 AAs), a sigmoidal DDD model reasonably allocated the native-like ß-hairpin structure with all-atom root mean square deviation (RMSD) = 2.0 Å as a global energy minimum. The optimal DDD condition was subsequently applied for Trp-cage (20 AAs) and its G10q mutant. The native-like α-rich folded structures with main-chain RMSD = 3.7 and 3.8 Å were obtained as global energy minima for Trp-cage and G10q, respectively. The results suggested that the REMC/SAAP3D method with the sigmoidal DDD model is useful for structural prediction for the short peptides comprised of up to 20 AAs. In addition, the relative contributions of SAAP to the total energy (%SAAP) were evaluated by energetic component analysis. The ratios of %SAAP were about 40 and 20% for chignolin and Trp-cage (or G10q), respectively. It was proposed that SAAP is more important for the secondary structure formation than for the assembly to a higher-order folded structure, in which the attractive van der Waals interaction may play a more important role.

Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide.

Single amino acid potential (SAAP) would be a prominent factor to determine peptide conformations. To prove this hypothesis, we previously developed SAAP force field for molecular simulation of polypeptides. In this study, the force field was renovated to SAAP3D force field by applying more accurate three-dimensional main-chain parameters, instead of the original two-dimensional ones, for the amino acids having a long side-chain. To demonstrate effectiveness of the SAAP3D force field, replica-exchange Monte Carlo (REMC) simulation was performed for two benchmark short peptides, chignolin (H-GYDPETGTWG-OH) and C-peptide (CHO-AETAAAKFLRAHA-NH2). For chignolin, REMC/SAAP3D simulation correctly produced native ß-turn structures, whose minimal all-atom root-mean-square deviation value measured from the native NMR structure (except for H) was 1.2 Å, at 300 K in implicit water, along with misfolded ß-hairpin structures with unpacked aromatic side chains of Tyr2 and Trp9. Similar results were obtained for chignolin analog [G1Y,G10Y], which folded more tightly to the native ß-turn structure than chignolin did. For C-peptide, on the other hand, the α-helix content was larger than the ß content on average, suggesting a significant helix-forming propensity. When the imidazole side chain of His12 was protonated (i.e., [His12Hip]), the α content became larger. These observations as well as the representative structures obtained by clustering analysis were in reasonable agreement not only with the structures of C-peptide that were determined in this study by NMR in 30% CD3CD in H2O at 298 K but also with the experimental and theoretical behaviors having been reported for protonated C-peptide. Thus, accuracy of the SAAP force field was improved by applying three-dimensional main-chain parameters, supporting prominent importance of SAAP for peptide conformations.