Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions

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• 作者：Ignacio Soteras Gutié ; rrez^b ; ^&dagger ; ; Fang-Yu Lin^a ; ^&dagger ; ; Kenno Vanommeslaeghe^a ; ^c ; Justin A. Lemkul^a ; Kira A. Armacost^d ; Charles L. Brooks III^d ; Alexander D. MacKerell Jr.^a ; ^{alex@outerbanks.umaryland.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Sigma hole ; Halogen bond ; CHARMM ; Halogen ; Drug design ; CGenFF
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：24
• 期：20
• 页码：4812-4825
• 全文大小：2773 K

文摘

A halogen bond is a highly directional, non-covalent interaction between a halogen atom and another electronegative atom. It arises due to the formation of a small region of positive electrostatic potential opposite the covalent bond to the halogen, called the ‘sigma hole.’ Empirical force fields in which the electrostatic interactions are represented by atom-centered point charges cannot capture this effect because halogen atoms usually carry a negative charge and therefore interact unfavorably with other electronegative atoms. A strategy to overcome this problem is to attach a positively charged virtual particle to the halogen. In this work, we extend the additive CHARMM General Force Field (CGenFF) to include such interactions in model systems of phenyl-X, with X being Cl, Br or I including di- and trihalogenated species. The charges, Lennard-Jones parameters, and halogen-virtual particle distances were optimized to reproduce the orientation dependence of quantum mechanical interaction energies with water, acetone, and N-methylacetamide as well as experimental pure liquid properties and relative hydration free energies with respect to benzene. The resulting parameters were validated in molecular dynamics simulations on small-molecule crystals and on solvated protein–ligand complexes containing halogenated compounds. The inclusion of positive virtual sites leads to better agreement across experimental observables, including preservation of ligand binding poses as a direct result of the improved representation of halogen bonding.