Biology - Computational Science Center Seminar

The mechanism in human dihydroorotate dehydrogenase (DHOD) involves both a proton and a hydride transfer reaction. One unresolved issue is whether the charge transfer reactions are sequential or concerted and, if sequential, the order of the two steps. Additionally, the pKa of serine implies that the local environment of this residue plays a key role in facilitating proton abstraction. To address these issues, we have chosen a mixed quantum classical approach, combining molecular dynamics simulations and quantum mechanical/molecular mechanical (QM/MM) calculations. Using QM/MM optimized geometries of the substrate and cofactor, we analyze several proton relay pathways involving the enzyme and the solvent with classical molecular dynamics simulations. We also investigate the effect of a mutation on the proton relay pathways by replacing the serine base with cysteine, where cysteine has been experimentally shown to significantly decrease enzyme activity. Our findings provide insight into the fundamental proton and hydride transfer mechanism at the active site of DHOD.