Improved pKa calculations through flexibility based sampling of a water-dominated interaction scheme
Improved pKa calculations through flexibility based sampling of a water-dominated interaction scheme
复制标题
DOI：
10.1110/ps.04785604
复制
发表时间：
2004-10-01
期刊：
影响因子：
8
通讯作者：
Warwicker, J
中科院分区：
文献类型：
--
作者：
Warwicker, J
可电离基团在生物过程中发挥着关键作用。 pK(a)S 的计算因模型近似和多种构象而变得复杂。对相对刚性的活性位点侧链的计算值和实验 pK(a) 进行比较，以开发电荷埋藏时水合熵变化的经验模型。发现修饰通常很小，但对于半胱氨酸来说很大，这与小分子电离数据以及电离和中性形式的部分电荷分布一致。水合模型预测了可电离残留物埋藏的显着熵贡献，这在丙酮酸脱氢酶复合物中的成分中得到了证明。 pH 滴定中的构象弛豫通过最大侧链溶剂可及性的平均场评估来估计。所有可电离残基都在低蛋白质介电有限差分 (FD) 方案中相互作用，更灵活的基团还可以实现水介导的德拜-希克尔 (DH) 相互作用。 DH 方法倾向于匹配整体 pH 依赖性稳定性，而 FD 对于活性位点组可以更准确。侧链旋转异构体堆积的耐受性各不相同，定义了 DH 相互作用的途径，以及与获得的实验 pK(a) 的最佳拟合。新的 (FD/DH) 方法提供了一个快速计算框架，用于区分埋藏基团和溶剂可及基团，这在以前的工作中已经定性明显，并且对于混合的可电离残基组，pK(a) 计算得到了显着改进。其有效性还通过计算静电能的 pH 依赖性、恢复对折叠状态稳定性的有利贡献以及与结构基因组学相关的静电应变活性位点识别的显着改进（减少假阳性）来证明。
Ionizable groups play critical roles in biological processes. Computation of pK(a)S is complicated by model approximations and multiple conformations. Calculated and experimental pK(a)s are compared for relatively inflexible active-site side chains, to develop an empirical model for hydration entropy changes upon charge burial. The modification is found to be generally small, but large for cysteine, consistent with small molecule ionization data and with partial charge distributions in ionized and neutral forms. The hydration model predicts significant entropic contributions for ionizable residue burial, demonstrated for components in the pyruvate dehydrogenase complex. Conformational relaxation in a pH-titration is estimated with a mean-field assessment of maximal side chain solvent accessibility. All ionizable residues interact within a low protein dielectric finite difference (FD) scheme, and more flexible groups also access water-mediated Debye-Hiickel (DH) interactions. The DH method tends to match overall pH-dependent stability, while FD can be more accurate for active-site groups. Tolerance for side chain rotamer packing is varied, defining access to DH interactions, and the best fit with experimental pK(a)s obtained. The new (FD/DH) method provides a fast computational framework for making the distinction between buried and solvent-accessible groups that has been qualitatively apparent from previous work, and pK(a) calculations are significantly improved for a mixed set of ionizable residues. Its effectiveness is also demonstrated with computation of the pH-dependence of electrostatic energy, recovering favorable contributions to folded state stability and, in relation to structural genomics, with substantial improvement (reduction of false positives) in active-site identification by electrostatic strain.