Folding of the villin headpiece subdomain from random structures. Analysis of the charge distribution as a function of pH.
Folding of the villin headpiece subdomain from random structures. Analysis of the charge distribution as a function of pH.
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DOI：
10.1016/j.jmb.2004.04.002
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发表时间：
2004-06
影响因子：
5.6
通讯作者：
D. Ripoll;J. Vila;H. Scheraga
中科院分区：
文献类型：
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作者：
D. Ripoll;J. Vila;H. Scheraga
采用静电驱动蒙特卡罗方法研究了36残基绒毛头套子域的结构。采用ECEPP/3 （Empirical构象能程序for Peptides）力场，加上两种不同的连续溶剂化模型，分别描述了N和C端被阻断和未被阻断的链的构象能。在pH值为3.7的条件下，通过刚性几何和核磁共振衍生的约束条件，与从已发表的实验数据中获得的一组10个原生类结构进行比较，对从头算生成的构象集合进行了统计分析。这10个类原生结构满足核磁共振导出的约束条件。利用连续溶剂化模型和ECEPP/3生成的末端未阻塞绒毛头子结构域的整体构象，随后在pH 3.7下使用包含ECEPP/3的势函数和快速多网格边界元方法进行了评估。在pH 3.7时，在构象搜索中发现的最低能量构象满足距离和二面角约束的~ 70%，并且具有构成分子疏水核心主要部分的三个苯丙氨酸残基的特征填充。另一方面，在pH 3.7和pH 7.0条件下，对满足核磁共振衍生约束的10个类天然结构进行了计算，结果表明，随着pH的变化，每种氨基酸残基的电荷分布都发生了很大的变化。本研究的结果为了解疏水性、电荷-电荷相互作用和溶剂极化等相互作用对这种小α-螺旋蛋白稳定性的影响提供了基础。
The structure of the 36 residue villin headpiece subdomain is investigated with the electrostatically driven Monte Carlo method. The ECEPP/3 (Empirical Conformational Energy Program for Peptides) force field, plus two different continuum solvation models, were used to describe the conformational energy of the chain with both blocked and unblocked N and C termini. A statistical analysis of an ensemble of ab initio generated conformations was carried out, based on a comparison with a set of ten native-like structures derived from published experimental data, by using rigid geometry and NMR-derived constraints obtained at pH 3.7. The ten native-like structures satisfy the NMR-derived constraints. The whole ensemble of conformations of the terminally unblocked villin headpiece sub-domain, generated by using ECEPP/3 with a continuum solvation model, were subsequently evaluated at pH 3.7 with a potential function that includes ECEPP/3 combined with a fast multigrid boundary element method. At pH 3.7, the lowest-energy conformation found during the conformational search satisfies ∼70% of both the distance and the dihedral-angle constraints, and possesses the characteristic packing of three phenylalanine residues that constitute the main part of the hydrophobic core of the molecule. On the other hand, computations at pH 3.7 and pH 7.0 for the ten native-like structures satisfying the NMR-derived constraints indicate a substantial change in the charge distribution for each type of amino acid residue with the change in pH. The results of this study provide a basis to understand the effect of the interactions, such as hydrophobicity, charge–charge interaction and solvent polarization, on the stability of this small α-helical protein.