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.
Biomolecular Force Field Parameterization via Atoms-in-Molecule Electron Density Partitioning
No author metadata is attached to this paper.
Published 2016 in Journal of Chemical Theory and Computation
ABSTRACT
PUBLICATION RECORD
- Publication year
2016
- Venue
Journal of Chemical Theory and Computation
- Publication date
2016-04-08
- Fields of study
Medicine, Physics, Chemistry, Computer Science
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- atoms-in-molecule electron density partitioning
A scheme that divides an electron density into atom-centered contributions for extracting atomic properties from quantum calculations.
Aliases: atoms-in-molecule partitioning, AIM partitioning, electron density partitioning
- biomolecular force field parameterization
The process of assigning molecular mechanics parameters for biomolecules and related organic systems.
Aliases: force field parameterization, MM parameterization
- biomolecular modeling
Computational modeling of organic molecules, biomolecules, and protein-containing systems.
Aliases: molecular modeling of biomolecules
- environment-specific charges
Atomic partial charges assigned in a way that depends on the local molecular environment.
Aliases: environment dependent charges, local charges
- free energies of hydration
The thermodynamic free-energy change associated with transferring a molecule from vacuum or gas phase into water.
Aliases: hydration free energies
- lennard-jones parameters
Nonbonded force-field coefficients that control short-range repulsion and long-range dispersion in molecular mechanics models.
Aliases: LJ parameters, van der Waals parameters
- linear-scaling density functional theory
A density functional theory approach designed to keep computational cost approximately proportional to system size for large molecular systems.
Aliases: linear scaling DFT, LS-DFT
- pure liquids
Bulk liquid systems used as a test setting for comparing predicted thermodynamic properties against reference data.
Aliases: liquid properties
- relative binding free energies
Differences in binding free energy between ligands, used here to compare indole and benzofuran binding.
Aliases: RBFE
- t4 lysozyme l99a mutant
A protein mutant used as a binding test system for comparing ligand affinities.
Aliases: L99A mutant of T4 lysozyme, T4L L99A
REFERENCES
Showing 1-67 of 67 references · Page 1 of 1