Biomolecular simulation is a critical tool for analysis of biopolymer structure and dynamics, investigation of intermolecular interactions, and design of new ligands and drugs. Simulation, in turn, is absolutely dependent on accurate and efficient models of the underlying structural chemistry and energetics in terms of empirical energy functions (?force fields?). Force field technology is currently in the midst of a generational transition from traditional atom-based point charges towards more intricate and accurate potentials using better electrostatic models. This proposal will continue development of the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field for nucleic acids (NAs), and extend the coverage of the model to naturally and synthetically modified NA components. Coupled with our 2013 AMOEBA protein parameters, the new NA force field will provide a unified model for the most important biomolecular systems. Current NA force fields lag well behind their protein counterparts in their ability to accurately model even the most typical structures under physiological conditions. The next-generation AMOEBA NA force field promises to significantly improve the fidelity and range of nucleic acids modeling. Nucleic acids are the major information carrying molecules of life. Under this research project, we will investigate several key aspects of nucleic acids, and refine the AMOEBA force field. The structures and functions of NAs are highly dependent upon the salt environment. The interplay between RNA local structural dynamics and global/tertiary folding is an intriguing question being addressed experimentally. The ability to model binding energetics, and design small molecule drugs and synthetically modified oligonucleotides will be an important growth area for future medical advances. These studies will be carried out in close collaborations with experimental colleagues. Development of an accurate and transferable next-generation force field will open up new paths toward understand and prediction of the behavior of natural and designed nucleic acid molecules. Finally, adequate sampling of large structures over longer time scales is crucial for future molecular simulations. The proposed development of high-performance, open source, parallel computer software will enable widespread application of the AMOEBA force field to nucleic acids and related biomolecular systems.

Public Health Relevance

A next-generation nucleic acid force field (AMOEBA) has been developed for standard nucleic acids. The model will be extended to naturally and synthetically modified DNAs and RNAs, and applied to a series of current problems in nucleic acids biophysics. The AMOEBA force field incorporates sophisticated physical interactions, including many-body polarization, charge penetration and atomic multipole-based permanent electrostatic interactions, which are essential for predicting the structure, dynamics and interactions of highly charged nucleic acid molecules. The advancement achieved in this work will provide researchers with an improved ability to understand the physical principles underlying nucleic acid structure/function, and ability to design ligands and synthetically modified oligonucleotides for inhibition of nucleic acid function and disruption of nucleic acid/protein interfaces for diagnostic and therapeutic purposes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Lyster, Peter
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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
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
Aviat, FĂ©lix; Levitt, Antoine; Stamm, Benjamin et al. (2017) Truncated Conjugate Gradient: An Optimal Strategy for the Analytical Evaluation of the Many-Body Polarization Energy and Forces in Molecular Simulations. J Chem Theory Comput 13:180-190
Jing, Zhifeng; Qi, Rui; Liu, Chengwen et al. (2017) Study of interactions between metal ions and protein model compounds by energy decomposition analyses and the AMOEBA force field. J Chem Phys 147:161733
Wendel, Ben S; He, Chenfeng; Qu, Mingjuan et al. (2017) Accurate immune repertoire sequencing reveals malaria infection driven antibody lineage diversification in young children. Nat Commun 8:531
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

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