A major challenge in the field of drug discovery is the accuracy of force fields used to model potential drug leads such that their binding affinities can be reliably predicted. Here, we report progress on the development of new quantum mechanical force fields (QMFFs at both the semiempirical and ab initio QM levels with machine learning corrections) that are highly robust, and able to handle complex interactions important for drug design. The QMFFs developed here are a form of linear-scaling electronic structure method that uses a fragmentation approach to replace explicit orbital coupling between fragments with density-functionals that model non-bonded interactions (including full electrostatics, many-body polarization, exchange and dispersion interactions) and specialized “QM/MM boundary” methods for fragments separated by covalent bonds. A clean separation between intra- and interfragment interactions in this framework improved electrostatic interactions, polarization response properties, and non-electrostatic non-bonded interactions. Among these factors, electrostatic interactions are critically important for modulating binding strength and selectivity of inhibitors to their protein targets. The QMFF models accurately take two important effects accurately into account for electrostatic interactions, including the higher-order multipolar character and diffusivity of the molecular electron charge density. Whereas the ab initio QMFFs naturally take into account an accurate representation of the electron density and electrostatic potential through a Gaussian multipolar expansion, the semiempirical QMFFs contain multipolar mapping parameters that can be optimized to very closely reproduce the ab initio electrostatic potential. Through multipolar Gaussian mapping, semiempirical QMFFs are able to accurately reproduce the electrostatic potential of ab initio DFT even for sigma holes and cation-pi interactions, enabling increased predictive capability for drug design applications.

Next-generation quantum mechanical force fields for drug discovery

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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