w/ Prof. Charles L. Brooks III
University of Michigan
we are currently studying the evolution of novel enzyme function in a class of enzymes found in plants, bacteria and fungi called sesquiterpene synthases. The attainment of new catalytic functions from an existing protein scaffold is a major force guiding evolutionary change but one that is perhaps only beginning to be understood. Understanding the evolution of enzymatic function at a physicochemical level requires first that probable evolutionary paths that interconvert an enzyme's specific function from one to another be discovered and thus a functional landscape be defined. Through a landmark study of sesquiterpene synthases (O'Maille et al., Nature Chemical Biology, 2008) from Prof. Joseph Noel's group (HHMI, Salk Institute) in which a sesquiterpene synthase with specific function was modified through nine mutations to obtain a sesquiterpene synthase with a different specific function as well as characterizing all 512 different combinations of these nine residues, a functional landscape underlying the evolution of sesquiterpene chemical diversity was revealed. Notably, none of the nine residues has a direct contact with the substrate and no single amino acid is correlated with product distribution. Through a multi-disciplinary effort involving molecular phylogenetics and molecular dynamics simulations that employ both classical force fields and hybrid Quantum Chemical/Molecular Mechanical (QC/MM) methods, we have begun to elucidate how product specificity or alternatively promisicuity emerges through mutations.

w/ Dr. Martin Field
Institut de Biologie Structurale
our group has been working on adding new features to the pDynamo package including fine grain parallelization of the semiempirical molecular orbital (SMO) code, a particle mesh Ewald routine for hybrid QC/MM potential, tools for reparameterization of SMO methods, and graphical interfaces for the construction, simulation and analysis of enzyme reaction simulations.