MOLECULAR DYNAMICS SIMULATIONS OF BIOLOGICAL MACROMOLECULES

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Applied theoretical research on AIDS proteins and other molecules ofbiomedical interest as well as basic research involving macromolecules is in progress. Molecular dynamics simulations of AIDS proteins involve projects directly related to the NIH Intramural AIDS Targeted Antiviral Program. The general goal is to understand binding interactions with HIV-1 proteins in order to facilitate the design of drugs which may interfere with the spread of the virus. Important therapeutic targets under study include HIV-1 reverse transcriptase, HIV-1 protease, the HIV-1 envelope protein gp120, and the CD4 receptor protein found on certain host cells. Projects include modeling of leucine zippers in GCN4 and HIV-1 reverse transcriptase, simulations of HIV-1 protease monomer in solution, analysis of inhibitor binding to the active site of HIV-1 protease, and investigation of the mechanism of action of HIV-1 protease. Other applied research on molecules of biomedical interest uses molecular dynamics simulations to predict function or structures of peptides and proteins. Projects include modeling the metabolism-based transformation of myoglobin to an oxidase and the simulation of lattice vibrations in the L-alanine crystal. Basic research is under way to provide a better understanding of biochemical systems. Projects include studies of environmental effects on protein dynamics, a simulation study of interleukin 1-beta, comparison with crystallographic and NMR data, harmonic analysis of large systems, modeling and simulation of lipid bilayers (gel and crystal phases in particular), structural analysis of T4 lysozyme mutants in the harmonic limit, comparison of simulations on staphylococcal nuclease with NMR data, and the examination of long range deuterium isotope effects in C-13 NMR spectra.