Computational Study of Catalytic Mechanisms and Specificities of Serine-Carboxyl Peptidases

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The objective of this project is to apply molecular dynamics and free energy simulations along with hybrid quantum mechanical and molecular mechanical potential function in combination with experimental studies to understand serine-carboxyl peptidases (sedolisins), a recently characterized and poorly understood family of proteolytic enzymes. Sedolisins have altered catalytic triad and oxyanion hole compared to those from classical serine peptidases. They are present in a wide variety of organisms, including archaea, bacteria, molds, slime molds, amoebas, fishes and mammals and are active under acidic environments and often at high temperature. There are considerable uncertainties concerning the catalytic processes and origins of substrate specificities for sedolisins, and detailed investigations of these enzymes through integrated computational and experimental approaches are therefore of considerable importance. This family is also of particular interest from the point of view of enzyme catalytic mechanism, because it seems to exhibit a novel mechanism that combines the features of classical serine and aspartic peptidases. Crystallographic, mutagenesis and other experimental studies will be performed to confirm the predictions obtained from computer simulations. The new mechanistic principles and catalytic mechanism studied from this project will benefit the general biochemistry community and may have a fundamental impact on understanding enzymes. The broader impacts of this project are diverse. The PI will integrate the research activities with education at different levels. Graduate and undergraduate students, including those from underrepresented groups, involved in this project will receive training and they will be invited to go to one of the nations premier national laboratories to interact with experimentalists. The opportunity to collaborate with the outstanding Japanese experts in the field of serine-carboxyl peptidases will add an international dimension and provide additional benefits to the research and educational activities. The PI will interact closely with the students at local high schools. High school students will have the opportunity to do research in the PIs lab through a variety of programs. This activity will enhance the learning experience of high school students and encourage them to pursue science as their careers. The PI will develop a website for understanding enzyme mechanisms and protein conformational changes, and this will make the teaching and learning processes much easier.