This project intends to apply methods of theoretical chemistry and statistical methodologies to the study of biomolecular structures and interactions. Systems of interest include the p2l product of the ras oncogene, mammalian p450 enzymes, and the HIV protease. Methods of approach include quantum calculations as well as classical force field approaches, database searching techniques, and molecular graphics. The p2l protein is a molecular """"""""switch"""""""" central to a variety of growth and developmental signaling pathways in human tissues. So far, our interest has focused on the catalytic transition from the active or signal transmitting GTP bound to the inactive GDP bound state, with emphasis on the effect of oncogenic mutants on this transition. The available experimental information has left crucial questions unanswered. We are modeling mammalian p450's using the homologous bacterial proteins. These enzymes as a class interact with a wide variety of substrates, and yet their specificity can be finely tuned by specific amino acid substitutions. In the absence of a known structure of a mammalian p450 we are focusing on a geometric model of the binding pocket. The HIV-l protease catalyzes the precise clipping of the polyprotein precursor to the mature viral particle. Its essential role in the viral life cycle has made it the target of intensive inhibitor design efforts. We have begun efforts to apply theoretical approaches to modified metal based inhibitors with the goal of optimizing binding and inhibitory effect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES043010-09
Application #
3755424
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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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