This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are interested in the mechanisms of enzymatic reactions and the dynamics of the carbohydrate-enzyme complexes. We are currently studying the dynamics of Golgi alpha-mannosidase II (GMII) complexed with mannostatin and aminocyclopentitetrol by employing MD simulations. Inhibition of the mannose-trimming enzyme GMII blocks the oncogene-induced changes in cell surface oligosaccharides. It is anticipated that further understanding of the interactions involving GMII will enhance development of more potent and selective inhibitors of GMII. We have also performed ligand docking to investigate possible additional binding modes of these ligands. The computed binding modes will help in designing combinatorial libraries to achieve selective inhibition of GMII. In addition to the dynamics, we are also simulating the hydrolysis reaction catalyzed by GMII using QM methods. These studies include determination of the preferred reaction coordinate and geometries of the intermediates involved in the hydrolysis, such as the transition state. This will be useful in designing transition state analogs, which will serve as more potent and selective inhibitors of GMII.
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