Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan; Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan; Department of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya, Aichi 463-8521, Japan.
Biochim Biophys Acta Proteins Proteom. 2020 Oct;1868(10):140480. doi: 10.1016/j.bbapap.2020.140480. Epub 2020 Jun 26.
The isomerization rate of aspartic acid (Asp) residue is known to be affected by the three-dimensional structures of peptides and proteins. Although the isomerized Asp residues were experimentally observed, structural features which affect the isomerization cannot be elucidated sufficiently because of protein denaturation and aggregation. In this study, molecular dynamics (MD) simulations were conducted on three αA-crystallin peptides (T6, T10, and T18), each containing a single Asp residue with different isomerization rate (T18 > T6 > T10) to clarify the structural factors of Asp isomerization tendency. For MD trajectories, distances between side-chain carboxyl carbon of Asp and main-chain amide nitrogen of (n + 1) residue (C-N distances), root mean square fluctuations (RMSFs), and polar surface areas for main-chain amide nitrogen of (n + 1) residues (PSA) were calculated, because these structural features are considered to relate to the formations of cyclic imide intermediates. RMSFs and PSA are indexes of peptide backbone flexibilities and solvent exposure of the amide nitrogen, respectively. The average C-N distances of T10 was longer than those of the other two peptides. In addition, the peptide containing Asp residue with a higher isomerization rate showed higher flexibility of the peptide backbone around the Asp residue. PSA for amide nitrogen in T18 were much larger than those of other two peptides. The computational results suggest that Asp-residue isomerization rates are affected by these factors.
天冬氨酸（Asp）残基的异构化速率已知受肽和蛋白质的三维结构影响。尽管已经实验观察到异构化的 Asp 残基，但由于蛋白质变性和聚集，无法充分阐明影响异构化的结构特征。在这项研究中，对三个 αA-晶体蛋白肽（T6、T10 和 T18）进行了分子动力学（MD）模拟，每个肽都含有一个异构化速率不同的单个 Asp 残基（T18>T6>T10），以阐明 Asp 异构化倾向的结构因素。对于 MD 轨迹，计算了侧链羧酸碳与（n+1）残基主链酰胺氮之间的距离（C-N 距离）、均方根波动（RMSF）和（n+1）残基主链酰胺氮的极性表面积（PSA），因为这些结构特征被认为与环状酰亚胺中间体的形成有关。RMSF 和 PSA 分别是肽骨架柔韧性和酰胺氮溶剂暴露的指标。T10 的平均 C-N 距离长于其他两个肽。此外，含有异构化速率较高的 Asp 残基的肽显示出 Asp 残基周围肽骨架更高的柔韧性。T18 中酰胺氮的 PSA 远大于其他两个肽。计算结果表明，Asp 残基的异构化速率受这些因素影响。
