The Nay Science

Adluri, Vishwa; Bagchee, J.

doi:10.1093/acprof:oso/9780199931347.001.0001

Cited by 55 publications

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“…[42][43][44] With the above additive and Drude polarizable FFs, improved treatment of halogens has involved attaching a charged virtual particle to the halogen to mimic the σ-hole in halogen and adequately reproduce XBs. 13,20,23,24,45,46 An important feature of halogens is their asymmetric van der Waals (vdW) surface associated with the shift of the electron density resulting in a shorter electron repulsion distance along the halogen linear to the C-X bond. 47 Moreover, a recent study indicates that the vdW contribution of halogens could significantly affect ligand-protein binding energies.…”

Section: Introductionmentioning

confidence: 99%

Improved Modeling of Halogenated Ligand–Protein Interactions Using the Drude Polarizable and CHARMM Additive Empirical Force Fields

Lin

MacKerell

2018

J. Chem. Inf. Model.

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Halogenated ligands can participate in nonbonding interactions with proteins via halogen bond (XB) or halogen-hydrogen bond donor (X-HBD) interactions. In the context of molecular dynamics (MD) simulations, the accuracy of the simulations depends strongly on the force field (FF) used. To assure good reproduction of XB and X-HBD interactions with proteins, we optimized the previously developed additive CHARMM36/CHARMM General force field (CGenFF) and Drude polarizable force field by including atom pair-specific Lennard-Jones parameters for aromatic halogen-protein interactions. The optimization targeted quantum mechanical interaction energy surfaces with the developed parameters then examined for their ability to reproduce experimental halogen-containing ligand-protein interactions in MD simulations. The calculated halogenated ligand interaction geometries were in good overall agreement with the experimental crystal data for both the polarizable and additive FFs, showing that these models can accurately treat both XB and X-HBD interactions. Analysis of the ligandprotein interactions shows significant contributions of polarizability to binding occurring in the Drude FF, with self-polarization energy making both favorable and unfavorable contributions to binding. Further analysis of the dipole moments from aqueous solution to protein indicates the polarizable FF accounts for subtle changes of the environment of the ligands that can impact binding. The present work demonstrates the utility of the updated additive CHARMM36/CGenFF and polarizable Drude FFs for the study of halogenated ligand-protein interactions in computeraided drug design.

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