Yeager Andrew V, Swails Jason M, Miller Bill R
Department of Chemistry, Truman State University , 100 E. Normal Ave., Kirksville, Missouri 63501, United States.
Department of Chemistry and Chemical Biology and BioMaPS Institute, Rutgers University , Piscataway, New Jersey 08854, United States.
J Chem Theory Comput. 2017 Oct 10;13(10):4624-4635. doi: 10.1021/acs.jctc.7b00638. Epub 2017 Sep 29.
The accuracy of computational models for simulating biomolecules under specific solution pH conditions is critical for properly representing the effect of pH in biological processes. Constant pH (CpH) simulations involving implicit solvent using the AMBER software often incorrectly estimate pK values of aspartate and glutamate residues due to large effective radii stemming from the presence of dummy protons. These inaccuracies stem from problems in the sampled ensembles of titratable residues that can influence other observable pH-dependent behavior, such as conformational change. We investigate new radii assignments for atoms in titratable residues with carboxylate groups to mitigate the systematic overestimation in the current method. We find that decreased carboxylate radii correspond with increased agreement with experimentally derived pK values for residues in hen egg-white lysozyme and Δ+PHS variants of staphylococcal nuclease (SNase) and improved conformation state sampling compared to experimentally described expectations of native-like structure. Our CpH simulations suggest that decreasing the effective radii of these carboxylate groups is essential for eliminating a significant source of systematic error that hurts the accuracy of both conformational and protonation state sampling with implicit solvent.
在特定溶液pH条件下模拟生物分子的计算模型的准确性对于正确呈现pH在生物过程中的影响至关重要。使用AMBER软件进行涉及隐式溶剂的恒定pH(CpH)模拟时,由于虚拟质子的存在导致有效半径较大,常常会错误地估计天冬氨酸和谷氨酸残基的pK值。这些不准确之处源于可滴定残基采样集合中的问题,这些问题会影响其他可观察到的pH依赖性行为,例如构象变化。我们研究了具有羧基的可滴定残基中原子的新半径分配,以减轻当前方法中的系统性高估。我们发现,与蛋清溶菌酶中的残基以及葡萄球菌核酸酶(SNase)的Δ+PHS变体相比,羧基半径减小与实验得出的pK值的一致性增加,并且与实验描述的天然样结构预期相比,构象状态采样得到改善。我们的CpH模拟表明,减小这些羧基的有效半径对于消除一个严重的系统误差来源至关重要,该误差源会损害隐式溶剂下构象和质子化状态采样的准确性。