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. Dr. Stan's research focuses on chaperonin-mediated protein folding. The double-ringed structured chaperonin GroEL and the cochaperonin GroES behave like an annealing nanomachine that assists in the folding of natural substrate proteins (SPs) under non-permissive conditions. The ``minichaperone'', containing only the isolated apical domain of GroEL, can assist folding of a certain class of proteins. To understand the annealing function of the minichaperone, at the molecular level, we have carried out molecular dynamics simulations for three systems, namely, the isolated strongly binding peptide (SBP), the minichaperone, and the SBP in complex with the minichaperone. Based on these simulations, we proposed that the minimal annealing action of the chaperonin system consists of a Transient Binding Release (TBR) mechanism. The TBR model suggests it that any cofactor that can repeatedly bind and release SPs can be effective in assisting protein folding. Dr. Klauda's research consists of three areas; structural and dynamical behavior of interfacial systems and lipids (collaboration with Dr. Richard Pastor of the FDA), membrane proteins, and protein folding. The aliphatic portion of the C27 force field was improved (C27r) and adjacent gauche states in alkanes were found to be stabilizing with implications to polymer models and conformational analysis. The same high-level quantum mechanical calculations on model lipid compounds are used to improve the force field parameters for the lipid head group (C27rg). Molecular dynamics on DPPC and DMPC bilayers with C27rg resulted in improved agreement with experimental NMR deuterium order parameters and 13C NMR relaxation times. Collaboration with the experimental group of Prof. John Nagle (CMU) resulted in the development of a new structural model, which can be used to determine the structure of liquid crystalline lipid bilayers from experiment. We have also developed a model-free approach to determine the surface area per lipid for pure, mixed lipids, and lipid-protein bilayers. Separately, interfacial systems, i.e., alkane-water, water-air, and lipid bilayers, have been studied using the newly developed Isotropic Periodic Sum (IPS) method by Dr. Xiongwu Wu. The work has demonstrated the benefit of IPS in accurately and efficiently obtaining long-range energies required in these simulations. The mechanism and protein structural response to sugar transport in lactose permease of E. coli., a membrane protein, is being studied with molecular dynamical simulations of the protein embedded in a POPE bilayer. Different sugar-protein contacts are found to be important in the wild-type protein compared to the structurally determined mutated protein. Dr. Zheng's research aims to study the coupling between the global dynamics of a large protein complex and the local dynamics of its functional site (such as a ligand-binding site), we have introduced a structural deformation of the functional site (mimicking ligand-binding), and then computed the induced conformational changes of the whole protein. This calculation has two applications: first, predict ligand-binding induced inter-domain motions; second, obtain an effective Hamiltonian for the functional site residues by ?integrating out? the remaining degrees of freedom and then solve the local modes to describe the local dynamics of the functional site. For application, we have analyzed the coupling of dynamics between the nucleotide-binding site and the whole myosin/kinesin motor domains, which has shed light on the signaling pathway that transmits the deformation at the nucleotide-binding site to the force-generating subdomains in these motor proteins. Dr Che uses computing and organic synthesis to explore fundamental problems in molecular recognition inspired by the biological world. Using his creative biomimetic approach, we have successfully design small molecules capable of mimicking protein surfaces recognized by other macromolecules, transition states of enzymatic reactions, and active sites of enzymes. These cell-permeable synthetic molecules may have applications as cellular probes and therapeutic agents such as drugs. The projects include successful design of following small molecules: 1. Modulators of protein-protein interactions ? For modulating protein-protein interactions, general approaches for mimicking protein surfaces would represent a significant advance. Protein recognition motifs comprise helices, sheets, turns, and polyproline II conformations in an apparently unbiased manner, thus we have designed small molecules capable of mimicking of each of these surfaces. Especially, the innovative design and development of helix mimetics is widely regarded as a breakthrough. 2. Inhibitors of enzymes ? Transition states (transient conformations) fit enzymes as a key fits a lock; and transition state analogs (stable compounds) are specific and tight-binding inhibitors of enzymes. Already there are six enzymes inhibited by drugs that function as transition state analogs. As the continuing improvement in the understanding of transition states and the design of stable analogs, therapeutic applications of transition state analogs will be more frequent in the future. We have systematically examined transition states and stable analogs for 132 different enzymes covering every mechanistic class. 3. Enzyme mimetics ? Low molecular-weight catalysts that mimic a natural enzymatic function have potential utility for the treatment of diseases characterized by the overproduction of a deleterious metabolic by-product or foreign gene product. We have successfully elucidated the mechanism, selectivity, and stability of nonpeptidyl functional mimetics of superoxide dismutase using ab initio calculations. In addition, we suggest that pentaazacrowns mimic active sites of heme-containing proteins. Using this concept, we have designed small catalysts to catalyze novel chemical reaction, namely the region- and chemo-specific nitration of phenol. Dr. Woodcock's research involves the investigation of carbohydrate structure, specifically the conformational properties of glucose analogs and examining the effects that solvation has on these systems. An ongoing collaboration with the group of Dr. Daron Freedberg and involves investigating the structural parameters of glucose (determined via NMR) and exploring the various effects that lead to the observed structural characteristics. Mr. O'Brien's (University of Maryland, Chemical Physics Program) research has focused on early events in disease related protein aggregation. Computer simulations are used to study dimerization of a peptide fragment from the amyloidogenic Thransthyretin protein. The effects of sequence mutation, sequence shuffling, molecular confinement and crowding on this process are being investigated. Mr. Larkin's (University of Georgia, Department of Chemistry) research involves the application of Quantum Mechanical/Molecular Modelling(QM/MM) and Molecular Dynamics simulation techniques to the Class D family of beta-lactmases that are responsible for the catalyzed hydrolysis of the penicillin class of antibiotics. Specifically, the mechanism by which the lactam ring in the antibiotic meropenem is cleaved, is being investigated using our more recently developed Replica/Path method for the determination of reaction pathways.
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