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

Abstract

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.

Improved Modeling of Cation‐π and Anion‐Ring Interactions Using the Drude Polarizable Empirical Force Field for Proteins

“…Molecular mechanics (MM) minimum interaction energies and distances were determined using the QM gas phase optimized monomer structures from rigid scans with only the distance of interest varied, analogous to the first approach used in the QM calculations. As previously presented and in analogy to the QM calculations, the interactions energies are based on the total energy of the dimer minus the energy of the monomers following optimization of the Drude particle positions with the real atoms fixed. The minimization, which satisfies the Born‐Oppenheimer approximation, was performed using the steepest‐descent (SD) algorithm with a step size of 0.01 to a force gradient of 10 −2 kcal·mol −1 ·Å −1 followed by the adopted basis Newton–Raphson algorithm (ABNR) with a step size of 0.02 to a force gradient of 10 −5 kcal·mol −1 ·Å −1 to relax the Drude particles, while constraining all real atoms (e.g., applying the “CONS FIX” command in CHARMM) following which the constraints were removed, and the energies were calculated.…”

FFParam: Standalone package for CHARMM additive and Drude polarizable force field parametrization of small molecules

“…Lone pairs (LPs) are an integral part of the Drude FF which further diverges the centrosymmetric‐nature common to most additive FFs. While the Drude FF still uses the Lennard–Jones term to treat van der Waals interactions, the inclusion of LJ parameters on LP and Drude particles introduces an effective asymmetry into the vdW representation . In addition, LJ parameters for specific atom pairs, termed atom‐pair specific LJ parameters (i.e., NBFIX in CHARMM nomenclature) have been used extensively to improve the treatment of nonbond interactions .…”

“…In addition, LJ parameters for specific atom pairs, termed atom‐pair specific LJ parameters (i.e., NBFIX in CHARMM nomenclature) have been used extensively to improve the treatment of nonbond interactions . Using these capabilities the Drude FF has been shown to perform better on halogenated species and on protein–halogen interactions as compared to additive FF . However, the Drude FF is relatively young in comparison to additive FFs and the range of chemical space covered is mainly associated with large biomolecules.…”

“…While the Drude FF still uses the Lennard-Jones term to treat van der Waals interactions, the inclusion of LJ parameters on LP and Drude particles introduces an effective asymmetry into the vdW representation. [21,22] In addition, LJ parameters for specific atom pairs, termed atom-pair specific LJ parameters (i.e., NBFIX in CHARMM nomenclature) have been used extensively to improve the treatment of nonbond interactions. [17] Using these capabilities the Drude FF has been shown to perform better on halogenated species and on protein-halogen interactions as compared to additive FF.…”

“…[17] Using these capabilities the Drude FF has been shown to perform better on halogenated species and on protein-halogen interactions as compared to additive FF. [22] However, the Drude FF is relatively young in comparison to additive FFs and the range of chemical space covered is mainly associated with large biomolecules. Therefore, a significant extension of the Drude polarizable FF to a much wider range of chemical space is required.…”