During this fiscal year we devoted major effort to work aimed at introducing polarizability into molecular force fields. Much of the work involved examining multipole expansions as a way to build accuracy into force field calculations. In one of the published studies it was shown that both static and geometry-dependent multipole models are able to reproduce total molecular forces and torques with repect to ab initio, whereas geometry-dependent multipoles are necessary to reproduce ab initio atomic forces. In another published work, a finite field method for calculating spherical tensor molecular polarizability tensors by numerical derivatives of induced molecular multipole with respect to gradients of the electrostatic potential are developed for arbitrary l and l'. These developments should be useful for the development of newer force fields that can be used to more accurately describe bio-macromolecules. Finally, we have developed code for partitioning the electron density into atomic contributions within the Hirshfeld-Iterated scheme. The codes developed in these studies are freely available. In addition, most of the applications required by NIEHS scientists to perform molecular modeling and dynamics were carried out with some of the programs that we had contributed to create (for example: Amber). These applications involve (but not limited to) mutational studies of TTP, a protein involved in RNA degradation;Aprataxin, HIV reverse transcriptase, construction of human constitutively active receptor (hCAR), Pinobarbital binding to EGF receptor, modeling of DNA with the inclusion of some ribonucleotides in the sequence.

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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; 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
Wells, Melissa L; Perera, Lalith; Blackshear, Perry J (2017) An Ancient Family of RNA-Binding Proteins: Still Important! Trends Biochem Sci 42:285-296
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
Shizu, Ryota; Osabe, Makoto; Perera, Lalith et al. (2017) Phosphorylated Nuclear Receptor CAR Forms a Homodimer To Repress Its Constitutive Activity for Ligand Activation. Mol Cell Biol 37:
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
Schellenberg, Matthew J; Perera, Lalith; Strom, Christina N et al. (2016) Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2. Nucleic Acids Res 44:3829-44
Mueller, G A; Randall, T A; Glesner, J et al. (2016) Serological, genomic and structural analyses of the major mite allergen Der p 23. Clin Exp Allergy 46:365-76
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

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