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Hayik SA , Dunbrack R , Merz KM
Mixed Quantum Mechanics/Molecular Mechanics Scoring Function To Predict Protein-Ligand Binding Affinity
Journal of Chemical Theory and Computation. 2010 Oct;6(10) :3079-3091
PMID: ISI:000282840600008   
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Computational methods for predicting protein-ligand binding free energy continue to be popular as a potential cost-cutting method in the drug discovery process. However, accurate predictions are often difficult to make as estimates must be made for certain electronic and entropic terms in conventional force field based scoring functions. Mixed quantum mechanics/molecular mechanics (QM/MM) methods allow electronic effects for a small region of the protein to be calculated, treating the remaining atoms as a fixed charge background for the active site. Such a semiempirical QM/MM scoring function has been implemented in AMBER using the DivCon program and tested on a set of 23 metalloprotein-ligand complexes, where QM/MM methods provide a particular advantage in the modeling of the metal ion. The binding affinity of this set of proteins can be calculated with an R-2 of 0.64 and a standard deviation of 1.88 kcal/mol without fitting and an R-2 of 0.71 and a standard deviation of 1.69 kcal/mol with fitted weighting of the individual scoring terms. In this study we explore the use of various methods to calculate terms in the binding free energy equation, including entropy estimates and minimization standards. From these studies we found that using the rotational bond estimate of ligand entropy results in a reasonable R-2 of 0.63 without fitting. We also found that using the ESCF energy of the proteins without minimization resulted in an R-2 of 0.57, when using the rotatable bond entropy estimate.
Hayik, Seth A. Dunbrack, Roland, Jr. Merz, Kenneth M., Jr. Nih [gm044974, r01 gm84453, p30 ca006927] K.M.M. thanks the NIH (Grant GM044974) and R.D. thanks the NIH (Grants R01 GM84453 (R.D.) and P30 CA006927 (Fox Chase Cancer Center)) for financial support of this work. 66 Amer chemical soc; 1155 16th st, nw, washington, dc 20036 usa 662ux