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.
The specific aim for this allocation is to carry out computations modeling the effect of bound anesthetic on structure and functional dynamics of gloubular, water-soluble, enzymes such as firely lucierase, ketosteroid isomerase and calmoduline. The calculations will employ a combination of course-grained approaches, such as Gaussian Network Model and Anisotropic Network Model and high detail level ones, namely Molecular Dynamics and QM/MM. Based on preliminary results, the essential hypothesis to be tested is that anesthetic affects both protein stability and functional mobility, causing both local and global changes that lead to enzyme inhibition. The study will result in a signifcant insight into the basic mechanism of anesthetic action on protein targets, including (1) determination of the chemical character of binding preferred by general anesthetics, (2) identification of anesthetic binding sites in the aforementioned proteins and their spatial relation to the binding sites of native agonists/substrates; and (3) consequences of the anesthetic binding to the protein dynamics and stability of its native conformation. Some aspects of the study will significantly contribute to a better understanding of the nature of anesthetic binding to protein target. The compuational work be complemented by high-resolution NMR measurements performed by Drs. P. Tang and Y. Xu of the Department of Anesthesiology.
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