Polypeptide folding using Monte Carlo sampling, concerted rotation, and continuum solvation
Polypeptide folding using Monte Carlo sampling, concerted rotation, and continuum solvation
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DOI：
10.1021/ja0378862
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发表时间：
2004-02-18
影响因子：
15
通讯作者：
Jorgensen, WL
中科院分区：
文献类型：
--
作者：
Ulmschneider, JP;Jorgensen, WL
应用蒙特卡罗统计力学模拟中的高效协同旋转算法折叠三种多肽，U(1-17)T9D、α(1)和trpzip2，它们呈现天然的β-发夹和α-螺旋折叠。该方法包括柔性键合和二面角，并在驱动键和二面角的基础上应用高斯偏置来优化采样效率。水中的溶剂化采用广义Born(GBSA)模型。计算的两个β-发夹的折叠结构的最低能量流形与相应的核磁共振结构非常吻合。在a(1)肽的情况下，折叠的α-螺旋状态在分离时是不稳定的，在浓溶液和晶体中观察到的是低聚物。在低浓度下，计算的无规卷曲结构的偏好与核磁共振实验一致。本征态可以从扩展构象开始定位于高维能面，这一事实表明，本方法采样了构象空间的所有相关部分。带有GBSA溶剂模型的OPLS-AA力场也被发现在导致形成β转弯的两个肽的正确折叠结构和错误折叠结构的能量分离方面表现良好。
An efficient concerted rotation algorithm for use in Monte Carlo statistical mechanics simulations is applied to fold three polypeptides, U(1-17)T9D, alpha(1), and trpzip2, which exhibit native beta-hairpin and alpha-helix folds. The method includes flexible bond and dihedral angles, and a Gaussian bias is applied with driver bond and dihedral angles to optimize the sampling efficiency. Solvation in water is implemented with the generalized Born (GBSA) model. The computed lowest-energy manifolds for the folded structures of the two beta-hairpins agree closely with the corresponding NMR structures. In the case of the a(1) peptide, the folded alpha-helical state, which is observed as oligomers in concentrated solution and crystals, is not stable in isolation. The computed preference for random coil structures is in agreement with NMR experiments at low concentration. The fact that native states can be located on high dimensional energy surfaces starting from extended conformations shows that the present methodology samples all relevant parts of the conformational space. The OPLS-AA force field with the GBSA solvent model was also found to perform well in leading to clear energetic separation of the correctly folded structures from misfolded structures for the two peptides that form beta-turns.