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Biomolecular Force Field Parameterization via Atoms-in-Molecular Electron Density Partitioning

Lookup NU author(s): Dr Daniel ColeORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Molecular mechanics force fields, which are commonly used in biomolecular modeling and computer-aided drug design, typically treat nonbonded interactions using a limited library of empirical parameters that are developed for small molecules. This approach does not account for polarization in larger molecules or proteins, and the parametrization process is labor-intensive. Using linear-scaling density functional theory and atoms-in-molecule electron density partitioning, environment-specific charges and Lennard-Jones parameters are derived directly from quantum mechanical calculations for use in biomolecular modeling of organic and biomolecular systems. The proposed methods significantly reduce the number of empirical parameters needed to construct molecular mechanics force fields, naturally include polarization effects in charge and Lennard-Jones parameters, and scale well to systems comprised of thousands of atoms, including proteins. The feasibility and benefits of this approach are demonstrated by computing free energies of hydration, properties of pure liquids, and the relative binding free energies of indole and benzofuran to the L99A mutant of T4 lysozyme.

Publication metadata

Author(s): Cole DJ, Vilseck JZ, Tirado-Rives J, Payne MC, Jorgensen WL

Publication type: Article

Publication status: Published

Journal: Journal of Chemical Theory and Computation

Year: 2016

Volume: 12

Issue: 5

Pages: 2312-2323

Online publication date: 08/04/2016

Acceptance date: 08/04/2016

Date deposited: 11/07/2016

ISSN (print): 1549-9618

ISSN (electronic): 1549-9626

Publisher: American Chemical Society


DOI: 10.1021/acs.jctc.6b00027


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