Improving the Scoring of Protein鈥揕igand Binding Affinity by Including the Effects of Structural Water and Electronic Polarization

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• 作者：Jinfeng Liu ; Xiao He ; John Z. H. Zhang
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2013
• 出版时间：June 24, 2013
• 年：2013
• 卷：53
• 期：6
• 页码：1306-1314
• 全文大小：370K
• 年卷期：v.53,no.6(June 24, 2013)
• ISSN：1549-960X

文摘

Docking programs that use scoring functions to estimate binding affinities of small molecules to biological targets are widely applied in drug design and drug screening with partial success. But accurate and efficient scoring functions for protein鈥搇igand binding affinity still present a grand challenge to computational chemists. In this study, the polarized protein-specific charge model (PPC) is incorporated into the molecular mechanics/Poisson鈥揃oltzmann surface area (MM/PBSA) method to rescore the binding poses of some protein鈥搇igand complexes, for which docking programs, such as Autodock, could not predict their binding modes correctly. Different sampling techniques (single minimized conformation and multiple molecular dynamics (MD) snapshots) are used to test the performance of MM/PBSA combined with the PPC model. Our results show the availability and effectiveness of this approach in correctly ranking the binding poses. More importantly, the bridging water molecules are found to play an important role in correctly determining the protein鈥搇igand binding modes. Explicitly including these bridging water molecules in MM/PBSA calculations improves the prediction accuracy significantly. Our study sheds light on the importance of both bridging water molecules and the electronic polarization in the development of more reliable scoring functions for predicting molecular docking and protein鈥搇igand binding affinity.