Biomolecular modeling and simulation lies at the heart of physically inspired methods for understanding molecular biology and structural biochemistry. Empirical force fields have been approaching a generational transition over the past several years, moving away from well- established, well-tuned but intrinsically limited fixed point charge models towards more intricate and accurate polarizable potentials. This research proposes to extend the polarizable AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field to nucleic acid systems. Together with the current AMOEBA protein parameterization, this will provide a consistently derived model for the two major biopolymer classes. The required electrostatic parameter for nucleic acids will be derived from high-level quantum mechanical electronic structure calculations. In order to use AMOEBA for DNA and RNA systems, several new energy functions will be needed to treat currently neglected effects, such as charge transfer, penetration of electron densities, and damping of dispersion at short distance ranges. The resulting next-generation of the AMOEBA force field promises to significantly improve the accuracy of short-range interactions over other currently available force fields. Nucleic acids, and their interaction with ions, small molecules and proteins, underlie much of human biochemistry, physiology and genetics. This research will calibrate the AMOEBA nucleic acid potentials on a series of structural motifs, against drug-RNA binding data, and with respect to interactions with ions. The validated force field will then open future opportunities for modeling of transcription factor interactions with DNA, detailed binding calculations for aminoglycoside antibiotics with the ribosome, and similar problems not approachable at present with polarizable force fields.

Public Health Relevance

Computer-aided molecular modeling, in concert with advances in structural biology, holds promise for the future development of new therapeutic agents. The ability to design molecules to inhibit or enhance nucleic acid function, disrupt nucleic acid/protein interfaces, etc. arises from accurate modeling of the structure, energetics and dynamics of the biological components. The increased accuracy of the AMOEBA force field model for DNA and RNA should help facilitate drug design for important systems, such a ribosomal antibiotics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter C
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Washington University
Schools of Arts and Sciences
Saint Louis
United States
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Laury, Marie L; Wang, Zhi; Gordon, Aaron S et al. (2018) Absolute binding free energies for the SAMPL6 cucurbit[8]uril host-guest challenge via the AMOEBA polarizable force field. J Comput Aided Mol Des 32:1087-1095
Zhang, Changsheng; Lu, Chao; Jing, Zhifeng et al. (2018) AMOEBA Polarizable Atomic Multipole Force Field for Nucleic Acids. J Chem Theory Comput 14:2084-2108
Qi, Rui; Jing, Zhifeng; Liu, Chengwen et al. (2018) Elucidating the Phosphate Binding Mode of Phosphate-Binding Protein: The Critical Effect of Buffer Solution. J Phys Chem B 122:6371-6376
Jing, Zhifeng; Liu, Chengwen; Qi, Rui et al. (2018) Many-body effect determines the selectivity for Ca2+ and Mg2+ in proteins. Proc Natl Acad Sci U S A 115:E7495-E7501
Bell, David R; Cheng, Sara Y; Salazar, Heber et al. (2017) Capturing RNA Folding Free Energy with Coarse-Grained Molecular Dynamics Simulations. Sci Rep 7:45812
Obliosca, Judy M; Cheng, Sara Y; Chen, Yu-An et al. (2017) LNA Thymidine Monomer Enables Differentiation of the Four Single-Nucleotide Variants by Melting Temperature. J Am Chem Soc 139:7110-7116
Harger, Matthew; Li, Daniel; Wang, Zhi et al. (2017) Tinker-OpenMM: Absolute and relative alchemical free energies using AMOEBA on GPUs. J Comput Chem 38:2047-2055
Zhang, Changsheng; Bell, David; Harger, Matthew et al. (2017) Polarizable Multipole-Based Force Field for Aromatic Molecules and Nucleobases. J Chem Theory Comput 13:666-678
Deng, Shi; Wang, Qiantao; Ren, Pengyu (2017) Estimating and modeling charge transfer from the SAPT induction energy. J Comput Chem 38:2222-2231
Han, Xu; Jing, Zhifeng; Wu, Wei et al. (2017) Biocompatible and blood-brain barrier permeable carbon dots for inhibition of A? fibrillation and toxicity, and BACE1 activity. Nanoscale 9:12862-12866

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