Is proton tunneling critical for enzyme function? It has been postulated in the scientific literature that the extraordinary catalytic ability of some biological enzymes is due to proton tunneling, which is thought to facilitate rearrangement of hydrogen atoms in the enzyme : substrate complex. Figure 1. Experimental crystal structure of the DHDPS enzyme In close collaboration with colleagues in the Department of Biological Sciences (Drs Juliet Gerrard and Renwick Dobson), we will use computational methods to elucidate the role that proton tunneling plays in the activity of dihydrodipicolinate synthase (DHDPS), a key enzyme in the biosynthesis of the amino acid lysine. This may involve any or all of the following: -­‐
-­‐
-­‐
-­‐
-­‐
-­‐
starting from the experimentally-­‐determined crystal structure of DHDPS, mapping out all possible reaction coordinates using Monte Carlo (random walk) methods, describing the energy of the system via a combination of quantum mechanics and molecular mechanics (QM/MM) calculating the reaction rate/s along each possible reaction coordinate using classical, semi-­‐classical and quantum dynamics simulations (this step may involve developing and/or implementing new methods to achieve the desired outcomes), and comparing with experiment exploring the effects of protonation state on reaction rates doing in silico mutagenesis studies, and comparing with existing experimental reaction rate data modeling inhibitor binding and designing new DHDPS inhibitors possibly developing new, more efficient models to more accurately model the potential energy surface of the system, if existing models are not accurate enough for quantitative prediction of reaction rates