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 - The study of the catalytic mechanism of D5-3-Ketosteroid Isomerase using QM/MM methods - The study of the catalytic mechanism of N-acetyltransferase using QM/MM methods - The study of the catalytic mechanism of Chorismate Mutase using QM/MM methods - Tracing the catalytic pathway of b-lactam hydrolysis - Determine the coding and promoter regions for the human gene NFAT5. - exploring methods for determining the inter-relatedness of a group of protein sequences. - Simulations of octyl glucoside micelles - Extend octyl glucoside simulations to the peptide Mastoparan X, a wasp venom - Determining which of the 13,500 genes in the Drosophila code for signal peptides Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of: - Chaperonin-mediated protein folding - 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 coiledcoils - Simulations of myoglobin and lysozyme crystals and solutions - Molecular dynamics simulations of CI2 Protein folding mediated by chaperonin molecules is studied using computer simulations. Our focus is on the GroEL-GroES chaperonin complex of the Escherichia coli, for which the associated structures are known. High-performance scientific computing methods are used, such as coarse-grained and all-atom descriptions of proteins in conjunction with the state-of-the-art CHARMM simulation program. These studies will shed light on the effect of chaperones on the protein structure, the mechanism of the chaperonin system, and the timescales in the chaperonin cycle. Ab initio calculations of NMR shielding tensors were performed for comparison with experimental studies for 1H and 15N nuclei. There was little correlation between calculated and experimental values for amide 1H, and role of factors such as basis set, and isotope effect were investigated as potential causes for the discrepancy. An 15N study is currently underway, using the 1H results as a starting point. Free energy calculations on the leucine zipper domain (GCN4-p1) of the yeast transcription factor GCN4 using Molecular Dynamics (MD) under physiological conditions and continuum models. The leucine zipper motif is a parallel left-handed supercoil composed of two a-helices. It is estimated that the native (parallel) alignment is energetically more stable than the non-native antiparallel alignment where electrostatic energies contribute significantly in the overall energetic picture of both orientation as well as to the preference of the parallel vs the antiparallel orientation. 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. Studying protein folding mechanism through SGMD simulation with all-atom model and explicit water. We have successfully observed two-state protein folding phenomena.
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