Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide
Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide
复制标题
SAAP3D力场的建立及其在木脂素和C肽复制交换蒙特卡罗模拟中的应用
DOI：
10.1007/s10822-017-0084-8
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Hirota Hiroshi
中科院分区：
文献类型：
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作者：
Iwaoka Michio;Suzuki Toshiki;Shoji Yuya;Dedachi Kenichi;Shimosato Taku;Minezaki Toshiya;Hojo Hironobu;Onuki Hiroyuki;Hirota Hiroshi
单氨基酸势（SAAP）将是决定肽构象的一个重要因素。为了证明这一假设，我们之前开发了用于多肽分子模拟的SAAP力场。在本研究中，对于具有长侧链的氨基酸，通过应用更精确的三维主链参数而不是原始的二维主链参数，将力场更新为SAAP3D力场。为了证明 SAAP3D 力场的有效性，对两种基准短肽：chignolin (H-GYDPETGTWG-OH) 和 C 肽 (CHO-AETAAAKFLRAHA-NH2) 进行了副本交换蒙特卡罗 (REMC) 模拟。对于牛油果素，REMC/SAAP3D 模拟正确生成了天然 β 转角结构，在 300 K 隐式水中，根据天然 NMR 结构（除 H 外）测得的最小全原子均方根偏差值为 1.2 Å，以及错误折叠的 β 发夹结构，其中 Tyr2 和 Trp9 的芳香族侧链未堆积。 chignolin 类似物 [G1Y,G10Y] 也获得了类似的结果，它比 chignolin 更紧密地折叠到天然 β 转角结构。另一方面，对于 C 肽，α 螺旋含量平均大于 β 含量，表明具有显着的螺旋形成倾向。当His12的咪唑侧链被质子化（即[His12Hip]）时，α含量变大。这些观察结果以及通过聚类分析获得的代表性结构不仅与本研究中在 298 K 的 30% CD3CD 水溶液中通过 NMR 测定的 C 肽结构相当一致，而且与已报告的质子化 C 肽的实验和理论行为一致。因此，通过应用三维主链参数提高了 SAAP 力场的准确性，支持了 SAAP 对于肽构象的突出重要性。
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 β-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 β-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 β-turn structure than chignolin did. For C-peptide, on the other hand, the α-helix content was larger than the β 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.