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Polarizable force field for RNA based on the classical drude oscillator.

ABSTRACT: RNA molecules are highly dynamic and capable of adopting a wide range of complex, folded structures. The factors driving the folding and dynamics of these structures are dependent on a balance of base pairing, hydration, base stacking, ion interactions, and the conformational sampling of the 2'-hydroxyl group in the ribose sugar. The representation of these features is a challenge for empirical force fields used in molecular dynamics simulations. Toward meeting this challenge, the inclusion of explicit electronic polarization is important in accurately modeling RNA structure. In this work, we present a polarizable force field for RNA based on the classical Drude oscillator model, which represents electronic degrees of freedom via negatively charged particles attached to their parent atoms by harmonic springs. Beginning with parametrization against quantum mechanical base stacking interaction energy and conformational energy data, we have extended the Drude-2017 nucleic acid force field to include RNA. The conformational sampling of a range of RNA sequences were used to validate the force field, including canonical A-form RNA duplexes, stem-loops, and complex tertiary folds that bind multiple Mg2+ ions. Overall, the Drude-2017 RNA force field reproduces important properties of these structures, including the conformational sampling of the 2'-hydroxyl and key interactions with Mg2+ ions. © 2018 Wiley Periodicals, Inc.

SUBMITTER: Lemkul JA

PROVIDER: S-EPMC6284239 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Polarizable force field for RNA based on the classical drude oscillator.

Lemkul Justin A JA MacKerell Alexander D AD

Journal of computational chemistry 20181201 32

RNA molecules are highly dynamic and capable of adopting a wide range of complex, folded structures. The factors driving the folding and dynamics of these structures are dependent on a balance of base pairing, hydration, base stacking, ion interactions, and the conformational sampling of the 2'-hydroxyl group in the ribose sugar. The representation of these features is a challenge for empirical force fields used in molecular dynamics simulations. Toward meeting this challenge, the inclusion of e ...[more]

PMID: 30515902

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Project description:A polarizable force field for nucleic acid bases based on the classical Drude oscillator model is presented. Parameter optimization was performed to reproduce crystallographic geometries, crystal unit cell parameters, heats of sublimation, vibrational frequencies and assignments, dipole moments, molecular polarizabilities and quantum mechanical base-base and base-water interaction energies. The training and validation data included crystals of unsubstituted and alkyl-substituted adenine, guanine, cytosine, uracil, and thymine bases, hydrated crystals, and hydrogen bonded base pairs. Across all compounds, the RMSD in the calculated heats of sublimation is 4.1%. This equates to an improvement of more than 2.5 kcal/mol in accuracy compared to the nonpolarizable CHARMM27 force field. However, the level of agreement with experimental molecular volume decreased from 1.7% to 2.1% upon moving from the nonpolarizable to the polarizable model. The representation of dipole moments is significantly improved with the Drude polarizable force field. Unlike in additive force fields, there is no requirement for the gas-phase dipole moments to be overestimated, illustrating the ability of the Drude polarizable force field to treat accurately differently dielectric environments and indicating the improvements in the electrostatic model. Validation of the model was performed on the basis of the calculation of the gas-phase binding enthalpies of base pairs obtained via potential of mean force calculations; the additive and polarizable models both performed satisfactorily with average differences of 0.2 and 0.9 kcal/mol, respectively, and rms differences of 1.3 and 1.7 kcal/mol, respectively. Overall, considering the number of significant improvements versus the additive CHARMM force field, the incorporation of explicit polarizability into the force field for nucleic acid bases represents an additional step toward accurate computational modeling of biological systems.

Dataset Information

Polarizable force field for RNA based on the classical drude oscillator.

Publications

Polarizable force field for RNA based on the classical drude oscillator.

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