Solvated Interaction Energy (SIE) for Scoring Protein-Ligand Binding Affinities. 1. Exploring the Parameter Space

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• 作者：Marwen Na&iuml ; m ; Sathesh Bhat ; Kathryn N. Rankin ; Sheldon Dennis ; Shafinaz F. Chowdhury ; Imran Siddiqi ; Piotr Drabik ; Traian Sulea ; Christopher I. Bayly ; Araz Jakalian ; Enrico O. Purisima
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2007
• 出版时间：January 2007
• 年：2007
• 卷：47
• 期：1
• 页码：122 - 133
• 全文大小：257K
• 年卷期：v.47,no.1(January 2007)
• ISSN：1549-960X

文摘

We present a binding free energy function that consists of force field terms supplemented by solvationterms. We used this function to calibrate the solvation model along with the binding interaction terms in aself-consistent manner. The motivation for this approach was that the solute dielectric-constant dependenceof calculated hydration gas-to-water transfer free energies is markedly different from that of binding freeenergies (J. Comput. Chem. 2003, 24, 954). Hence, we sought to calibrate directly the solvation terms inthe context of a binding calculation. The five parameters of the model were systematically scanned to bestreproduce the absolute binding free energies for a set of 99 protein-ligand complexes. We obtained a meanunsigned error of 1.29 kcal/mol for the predicted absolute binding affinity in a parameter space that wasfairly shallow near the optimum. The lowest errors were obtained with solute dielectric values of D_in = 20or higher and scaling of the intermolecular van der Waals interaction energy by factors ranging from 0.03to 0.15. The high apparent D_in and strong van der Waals scaling may reflect the anticorrelation of thechange in solvated potential energy and configurational entropy, that is, enthalpy-entropy compensation inligand binding (Biophys. J. 2004, 87, 3035-3049). Five variations of preparing the protein-ligand data setwere explored in order to examine the effect of energy refinement and the presence of bound water on thecalculated results. We find that retaining water in the final protein structure used for calculating the bindingfree energy is not necessary to obtain good results; that is the continuum solvation model is sufficient.Virtual screening enrichment studies on estrogen receptor and thymidine kinase showed a good ability ofthe binding free energy function to recover true hits in a collection of decoys.