The quality of the force field is crucial to ensure the accuracy of molecular modeling and simulations used in computer-aided drug design (CADD). The treatment of halogens by a force field is of particular importance to drug design as halogen atoms are able to form a halogen bond with hydrogen bond acceptors as well as act as hydrogen bond acceptors themselves. Due to these classes of interactions, incorporation of halogen atoms could potentially increase ligand selectivity and binding affinity. In this work, the polarizable force field based on the classical Drude oscillator model is extended to a series of halogenated molecules, including both aliphatic and aromatic systems, including benzene-X<sub>n</sub> and ethane-X<sub>n</sub> with X being F, Cl, Br or I and n = 1 - 3. The force field parameters were optimized targeting quantum mechanical data, including dipole moments, water interactions, and molecular polarizabilities as well as experimental observables, including enthalpies of vaporization, molecular volumes, hydration free energies, and dielectric constants. The developed force field shows better agreement across experimental condensed-phase properties compared to the additive CHARMM General Force Field and better reproduces protein-ligand binding geometries due to the explicit treatment of induced polarization and halogen bond interaction. The resulting polarizable force field will be applicable to halogenated derivatives of compounds of medicinal chemistry interest for use in CADD studies.

Parametrization of the drude polarizable force field for halogenated compounds

254th National Meeting (2017)

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