Electrostatic interactions play important roles in protein structure and function by affecting residue pKas, redox Ems and binding of charged molecules.  We are developing Monte Carlo simulation techniques to study the thermodynamics of proton, electron and ion binding and Network analysis of proton transport pathways. 

Bioenergetic proton pumps

Biology stores energy in the transmembrane electrochemical gradient.  Thus, moving electrons, protons, and ions through membrane-embedded proteins builds up a charge difference (∆V) and a difference in the concentration of protons (∆pH) and of other ions across the membrane.  We are especially interested in the function of the mitochondria and photosynthetic electron and proton transfer proteins.  We ask how the protein modifies the proton affinity and proton pathways through the reaction cycle of proton pumps.

A proton pump uses the energy of light (in photosynthesis) or metabolites (mitochondria and bacteria) to move protons from the high pH, negative, N-side of the membrane to the low pH, positive, P-side of the membrane.  A basic proton pump has several minimal requirements including: (1) a change in proton affinity during the reaction cycle so protons will be bound from the N-side and released to the P-side via transiently loaded sites in the protein interior, a process that is thermodynamically uphill; (2) a pathway for protons to be handed from donor to acceptor through the hydrophobic interior of the membrane embedded region of the protein via a Grotthuss mechanism; (3) a means to close off proton transport so that the interior is only accessible to the N-side during proton uptake into the protein and accessible to the P-side during release to keep protons from moving downhill.

We are currently studying Photosystem II, the type II bacterial photosynthetic reaction centers, Cytochrome c oxidase, NADH Q dehydrogenase, bacteriorhodopsin and the Cl/H antiporter. 

Software development

We develop the Monte Carlo program MCCE, which combines continuum electrostatics & molecular mechanics to study coupled conformation & ionization state changes in proteins. 

We analyze the effects of binding charged groups on the protonation states of ligand and protein.  Monte Carlo sampling within MCCE is being used to find the Boltzmann distribution of hydrogen bonds in possible proton transfer networks.