Exploring Catalytic Modules in Alkaline Phosphatase by Computer Simulation

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 DESCRIPTION (provided by applicant): The proposed research will use state-of-the-art computer simulations to examine fundamental processes of enzyme catalysis. A deep understanding of the physical mechanisms of enzyme catalysis will illuminate both the design of new catalysts, as well as drugs that inhibit enzymes. The proposal aims to understand a potentially important, novel aspect of catalysis by the enzyme alkaline phosphatase (AP). AP catalyzes phosphate transfer, which is one of the most important reactions in biology and medicine, and recent experiments proposed that the enzyme uses "functional modules" at the active site to catalyze the reaction. The functional modules, consisting of a few amino acids each, display a previously unobserved mode of cooperativity. The proposed computer simulations will determine how this cooperativity works at an atomic level and whether it could be important for other enzymes. Additionally, in order to accurately model this enzyme, the proposed research will develop an improved method for computer simulations of enzymes. Currently available methods falter in reactions involving highly charged substrates, and the proposed improvements to treating such reactions will have useful applications in enzymology.