This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The PI has been involved with molecular dynamics analyses of Acetylcholinesterase (AChE) since 1993, and other systems - some of which were performed at the PSC. This enzyme is critically involved in the transmission of nerve signals to muscle contraction, and it is the target of nerve gas agents as well as drugs used to treat Alzheimer(s disease. Fasciculin (Fas) is a component of snake venom that also targets AChE. A manuscript by Sussman et al, reviewed by the PI, and currently _in press_, reports that certain Fas mutants bind more avidly to AChE, but their affinity is not explained by examination of the static crystal structures. We have run CHARMm simulations of the AChE-Fas complex on a single-CPU SGI machine that suggest the discrepancies are a consequence of main chain distortions induced by the mutations. We are seeking PSC access to extend these CHARMm simulations and better explain why some mutations enhance, while others inhibit binding, contrary to predictions based on static analysis of the crystal structures. The conclusions will be relevant to many questions about protein design. The proposed studies will be performed by a graduate student in Biochemistry and Molecular Biophysics at the University of Pennsylvania, under the supervision of the PI. This student is already performing CHARMm simulations on in-house machines, so development time on PSC machines will be minimal. The project will continue until mid-September, or possibly December.
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