The goal of this project is to improve the quality of molecular modeling and molecular dynamics simulations, and to apply these methods to highly pertinent problems, both from the view of biomedical relevance and methodological challenge. In principle, molecular dynamics simulations offer a detailed atomic level description of the interactions between key biomoilecules of significance to human health. In practice, this methodology is limited by the short simulation times (less than 100 nanoseconds) available with current computer technology, which translates into limited conformational sampling, and by the inaccuracies in the empirical force fields used in the simulations. While a number of groups are attempting to relieve the conformational sampling bottlenecks, we are focusing on improvements to the accurracy of representations, without sacrificing computational efficiency. The long range goal is to do simulations from """"""""first principles"""""""", i.e. without resorting to empirical fitting procedures. This fiscal year we developed an efficient algorithm to evaluate interatomic electrostatics up to the level of atomic hexadecapoles, using a cartesian multipole formalism and including the possibility of induced polarizable dipoles. We also developed a multigrid Poisson solver for numerically evaluating the Ewald sum in the atomic multipole context. This latter approach, while not as efficient as PME on single or few processor machines, exhibits superior scaling in massively parallel machines. We have now successfully generalized these approaches to the case of atomic multipoles. Work on efficient implementation of a polarizable, multipolar protein force field is underway.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
United States
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Min, Jungki; Perera, Lalith; Krahn, Juno M et al. (2018) Probing Dominant Negative Behavior of Glucocorticoid Receptor ? through a Hybrid Structural and Biochemical Approach. Mol Cell Biol :
Li, Yin; Perera, Lalith; Coons, Laurel A et al. (2018) Differential in Vitro Biological Action, Coregulator Interactions, and Molecular Dynamic Analysis of Bisphenol A (BPA), BPAF, and BPS Ligand-ER? Complexes. Environ Health Perspect 126:017012
Perera, Lalith; Li, Yin; Coons, Laurel A et al. (2017) Binding of bisphenol A, bisphenol AF, and bisphenol S on the androgen receptor: Coregulator recruitment and stimulation of potential interaction sites. Toxicol In Vitro 44:287-302
Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2017) Hiding in Plain Sight: The Bimetallic Magnesium Covalent Bond in Enzyme Active Sites. Inorg Chem 56:313-320
Perera, Lalith; Freudenthal, Bret D; Beard, William A et al. (2017) Revealing the role of the product metal in DNA polymerase ? catalysis. Nucleic Acids Res 45:2736-2745
Almaliti, Jehad; Al-Hamashi, Ayad A; Negmeldin, Ahmed T et al. (2016) Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue. J Med Chem 59:10642-10660
Takaku, Motoki; Grimm, Sara A; Shimbo, Takashi et al. (2016) GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biol 17:36
Perera, Lalith; Freudenthal, Bret D; Beard, William A et al. (2015) Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse. Proc Natl Acad Sci U S A 112:E5228-36
Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2014) Applications of quantum mechanical/molecular mechanical methods to the chemical insertion step of DNA and RNA polymerization. Adv Protein Chem Struct Biol 97:83-113
Perdivara, Irina; Perera, Lalith; Sricholpech, Marnisa et al. (2013) Unusual fragmentation pathways in collagen glycopeptides. J Am Soc Mass Spectrom 24:1072-81

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