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, abinitio 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:- Tracing the catalytic pathway of beta-lactam hydrolysis- Free energy studies of beta-lactam binding- Molecular dynamics of native and mutant vnd/NK-2 homeodomain--DNA complexes- C3a anaphylatoxin and antibody binding sites- Protein structure stabilization and activity in human rhinovirus- Modeling the catalytic mechanism of adenosine kinase with QM/MM methods- Molecular dynamics simulation on NK/MHC I complex Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of:- Lipid bilayer gel phase simulations- Investigating the environmental dependence of nucleic acid structure- Modeling leucine zippers: Origins of parallel vs. antiparallel orientation of coiledcoils- Environmental dependence of protein dynamics: Myoglobin- The study of the catalytic mechanism of aldose reductase using QM/MM methods- Molecular dynamics simulations of CI2The use of the beta-lactam family of antibiotics, including penicillin and cephalosporin, is limited by the activity of the bacterias defensive b-lactamases. Although, the reaction mechanism has been well studied experimentally, the specific role and protonation states of the required and active site residues are still unclear. This project investigates the two suggested reaction mechanisms of Penicillin-G in TEM-1, a clinically prevalent beta-lactamase, using a hybrid quantum mechanical and classical treatment. These are very large calculations since preliminary work suggested that the QM region had to be expanded three times to include additional active site residues in the study because of their role in reducing barriers or their participation in a proton-shuttle mechanism. The current study has identified catalytic roles for conserved residues (S130, K243) in addition to their structural importance. The study also has shown that the protonation state of a conserved lysine (K73) is critical to determining the hydrolytic path. The study differentiates between two proposed mechanisms and confirms the low energy barriers to proton transfer if K73 is initially deprotonated. This is supported by Poisson-Boltzmann calculations which suggest that K73 is deprotonated due to adjacent charges, active site placement and the nearby terminus of the H3 alpha helix. - molecular dynamics, simulation, mechanism, theory, molecular graphics, quantum mechanics