Molecular Dynamics Simulations of Biological Macromolecules

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The Computational Biophysics Section studies problems of biological significance using several theoretical techniques: molecular dynamics, molecular mechanics, modeling, ab initio analysis of small molecule structure, and molecular graphics. These techniques are applied to a wide variety of macromolecular systems. Specific projects applied to molecules of biomedical interest uses molecular dynamics simulations to predict function or structures of peptides and proteins. Such projects include: - Reaction mechanisms of beta-lactam antibiotics - Simulation of a large virus complex, human rhino virus 14 (HRV14) - Lethal point mutations in homeodomain/DNA complexes: Investigation of the A43T mutation in vnd/NK-2 by simulation - Investigation of the mechanism of action of HIV-1 protease - Identification of peptides which bind to human MHC DR1 Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of: - Simulation of Nucleic Acids and NA/protein complexes - Dependence of simulated structure and dynamics on environmental considerations - Molecular dynamics simulations of staphylococcal nuclease and other proteins: comparison with NMR Data - Unbiased forced sampling of complex conformational transitions: Propagation of a B-DNA/Z-DNA junction. - Realistic representation of nucleic acids in solution. - Protein-protein Docking Study of C3a Anaphylatoxin - The study of the catalytic mechanism of aldose reductase using QM/MM methods - gel phase simulations of DPPC lipid bilayer, comparison with experiment - Comparison study of extreme thermophile and corresponding mesophile proteins - DNA/protein interactions: the sex-determining region of the human chromosome - Modeling the hammerhead ribozyme-substrate complex system - Modeling of leucine zippers using molecular dynamics The use of beta-lactam family of antibiotics, including penicillin and cephalosporin, is limited by the activity of the bacteria's defensive beta-lactamases. The reaction mechanism has been well studied experimentally but the specific role and protonation states of required residues are still unclear. This work traces the two suggested reaction mechanisms using a hybrid quantum and classical treatment in order to suggest the most probable path. Future work includes optimization of the beta-lactam substituents to reduce the rate of catalysis.