Additive CHARMM36 Force Field for Nonstandard Amino Acids.

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TitleAdditive CHARMM36 Force Field for Nonstandard Amino Acids.
Publication TypeJournal Article
Year of Publication2021
AuthorsCroitoru, A, Park, S-J, Kumar, A, Lee, J, Im, W, Mackerell, AD, Aleksandrov, A
JournalJ Chem Theory Comput
Volume17
Issue6
Pagination3554-3570
Date Published2021 Jun 08
ISSN1549-9626
Abstract

Nonstandard amino acids are both abundant in nature, where they play a key role in various cellular processes, and can be synthesized in laboratories, for example, for the manufacture of a range of pharmaceutical agents. In this work, we have extended the additive all-atom CHARMM36 and CHARMM General force field (CGenFF) to a large set of 333 nonstandard amino acids. These include both amino acids with nonstandard side chains, such as post-translationally modified and artificial amino acids, as well as amino acids with modified backbone groups, such as chromophores composed of several amino acids. Model compounds representative of the nonstandard amino acids were parametrized for protonation states that are likely at the physiological pH of 7 and, for some more common residues, in both d- and l-stereoisomers. Considering all protonation, tautomeric, and stereoisomeric forms, a total of 406 nonstandard amino acids were parametrized. Emphasis was placed on the quality of both intra- and intermolecular parameters. Partial charges were derived using quantum mechanical (QM) data on model compound dipole moments, electrostatic potentials, and interactions with water. Optimization of all intramolecular parameters, including torsion angle parameters, was performed against information from QM adiabatic potential energy surface (PES) scans. Special emphasis was put on the quality of terms corresponding to PES around rotatable dihedral angles. Validation of the force field was based on molecular dynamics simulations of 20 protein complexes containing different nonstandard amino acids. Overall, the presented parameters will allow for computational studies of a wide range of proteins containing nonstandard amino acids, including natural and artificial residues.

DOI10.1021/acs.jctc.1c00254
Alternate JournalJ Chem Theory Comput
PubMed ID34009984
PubMed Central IDPMC8207570
Grant ListR01 GM138472 / GM / NIGMS NIH HHS / United States
R35 GM131710 / GM / NIGMS NIH HHS / United States