First conceived in the 1950s and advanced through the latter half of the 20th century, molecular dynamics simulations have become a key branch of computer aided drug discovery. The ability to calculate the evolution of atomic positions through time, based on an underlying molecular mechanic energy function, brought with it the potential to explore dynamic ensembles of biomolecular drug targets, and to gain mechanistic understanding of drug interactions at an atomic level. Significant contributions to the field have been made by Karplus and MacKerell, who have been responsible for the development of the popular CHARMM MD software and force fields (the potential energy function and parameters used as the underlying model) (https://doi.org/10.1002/jcc.540040211). The first CHARMM force field (CHARMM19) was developed in the 1980s and used an united-atom representation (where implicit hydrogens were treated as part of the attached heavy atom) (https://doi.org/10.1063/1.472061). Since then, multiple re-parameterisations, corrections and additions, where parameters were fitted to experimental structure and ab inito data, have been released (https://doi.org/10.1021/jp973084f). Today, the CHARMM force fields utilises an all-atom model that incorporates bonded and non-bonded potential energy terms and parameters for the basic biochemical building blocks; e.g the standard amino acids, phospholipids, and nucleic acids (https://doi.org/10.1038/nmeth.4067). In addition, the CHARMM general force field (CGenFF) allows users to fit parameters to a wide range of small molecules based on the chemical groups and atom types present in the structure, which crucially allows researchers to model the interactions of small molecules with biomolecular targets (https://doi.org/10.1002/jcc.21367).
CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
Journal of Computational Chemistry, 1983, 4, 187-217.
Simulation of activation free energies in molecular systems
J. Chem. Phys. 105, 1902 (1996)
CHARMM36m: an improved force field for folded and intrinsically disordered proteins
Nature Methods volume 14, 2016, pages 71–73
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
Journal of Computational Chemistry, 2010, 31, 671-690.
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