Protocols Utilizing Constant pH Molecular Dynamics to Compute pH-Dependent Binding Free Energies

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• 作者：M. Olivia Kim ; Patrick G. Blachly ; Joseph W. Kaus ; J. Andrew McCammon
• 刊名：Journal of Physical Chemistry B
• 出版年：2015
• 出版时间：January 22, 2015
• 年：2015
• 卷：119
• 期：3
• 页码：861-872
• 全文大小：436K
• ISSN：1520-5207

文摘

In protein鈥搇igand binding, the electrostatic environments of the two binding partners may vary significantly in bound and unbound states, which may lead to protonation changes upon binding. In cases where ligand binding results in a net uptake or release of protons, the free energy of binding is pH-dependent. Nevertheless, conventional free energy calculations and molecular docking protocols typically do not rigorously account for changes in protonation that may occur upon ligand binding. To address these shortcomings, we present a simple methodology based on Wyman鈥檚 binding polynomial formalism to account for the pH dependence of binding free energies and demonstrate its use on cucurbit[7]uril (CB[7]) host鈥揼uest systems. Using constant pH molecular dynamics and a reference binding free energy that is taken either from experiment or from thermodynamic integration computations, the pH-dependent binding free energy is determined. This computational protocol accurately captures the large pK_a shifts observed experimentally upon CB[7]:guest association and reproduces experimental binding free energies at different levels of pH. We show that incorrect assignment of fixed protonation states in free energy computations can give errors of >2 kcal/mol in these host鈥揼uest systems. Use of the methods presented here avoids such errors, thus suggesting their utility in computing proton-linked binding free energies for protein鈥搇igand complexes.