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.

Project Start
Project End
Budget Start
Budget End
Support Year
27
Fiscal Year
2012
Total Cost
$336,096
Indirect Cost
City
State
Country
Zip Code
Takaku, Motoki; Grimm, Sara A; Roberts, John D et al. (2018) GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network. Nat Commun 9:1059
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 :
Jongwattanapisan, Prapaporn; Terajima, Masahiko; Miguez, Patricia A et al. (2018) Identification of the effector domain of biglycan that facilitates BMP-2 osteogenic function. Sci Rep 8:7022
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
Samaradivakara, Saroopa P; Samarasekera, Radhika; Handunnetti, Shiroma M et al. (2018) A Bioactive Resveratrol Trimer from the Stem Bark of the Sri Lankan Endemic Plant Vateria copallifera. J Nat Prod 81:1693-1700
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
Wells, Melissa L; Perera, Lalith; Blackshear, Perry J (2017) An Ancient Family of RNA-Binding Proteins: Still Important! Trends Biochem Sci 42:285-296
Zheng, Xunhai; Mueller, Geoffrey A; Kim, Kyungmin et al. (2017) Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase. Biochem J 474:3321-3338
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:

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