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:- 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- Tracing the catalytic pathway of b-lactam hydrolysis Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of:- NMR Shielding Tensor calculations- Lipid bilayer gel phase simulations- Investigating the environmental dependence of nucleic acid structure- Modeling leucine zippers: Origins of parallel vs. antiparallel orientation of coiled coils- Environmental dependence of protein dynamics: Myoglobin- The study of the catalytic mechanism of aldose reductase using QM/MM methods- Molecular dynamics simulations of CI2Ab initio calculations of NMR shielding tensors are being performed for comparison with experimental studies for 1H and 15N nuclei. Currently, there is little correlation between calculated and experimental values for 1H, and role of factors such as basis set, and isotope effect are under investigation as potential causes for the discrepancy. Once the role of these factors are assessed for 1H, the results will be applied to the 15N calculation. Molecular Dynamics studies of the parallel a-helical coiled-coil GCN4p1 and antiparallel seryl tRNA synthetase (STS) have been performed and replica annealing method have been utilized to investigate hydrophobic interactions and their impact on helix orientation (parallel vs antiparallel) using Solvation Free Energy estimates and Surface Area analysis. Poisson-Boltzmann calculations on electrostatic interactions of parallel a-helical leucine zipper GCN4p1 coiled-coil in solution are used to estimate solution dimerization energies. These are examined to determine the factors influencing helical orientation (parallel vs antiparallel) and stability in processing the results of Molecular Dynamics studies. The phosphorylation of adenosine by ATP is catalyzed by Adenosine Kinase. The different pathways in which the mechanism can proceed are being worked out by using quantum mechanical/molecular mechanical techniques. Using our double link atom method with gaussian blur, we have calculated the acidity of the 5' alcohol of adenosine and the proton affinity of aspartate. These are crucial steps in the overall mechanism and provides confidence that our QM/MM method will provide reasonable answers while studying the entire system.
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