Robert Cukier
Professor Office: 34 Chemistry
Phone: 517-355-9715 263 /
Websites: Research Group - Area
Awards & Honors
Genealogy/Graduates
Theories of Charge Transfer and Transport
(Research Description PDF - 1140 kb)We use methods of Statistical Mechanics and Quantum Mechanics to create theories of and design computational algorithms for the simulation of protein structure-function relations. Ongoing studies include proton coupled electron transfer, proton translocation, large-scale domain movements, ligand docking, and reaction mechanisms in enzymes.
Respiration and photosynthesis rely on electron, proton, and proton-coupled electron transfer reactions that take place in enzyme active sites. Electrons and protons should be treated by quantum mechanics and, because they are charged, they strongly interact with surrounding polar amino acids. In cytochrome c oxidase, chains of hydrogen bonded water and/or amino acid residues are essential to proton translocation, the movement of protons across a membrane, to build up an electrochemical gradient for energy transduction. We develop computer codes to carry out quantum molecular dynamics simulations that couple the quantum electron and/or protons to the surrounding classically-treated (by molecular dynamics) atoms. The formation of chains of hydrogen bonded waters in proteins can be investigated by these simulations. An example of such chain formation in cytochrome c oxidase is displayed in the figure at right.
Some proteins, such as adenylate kinase (AK), that catalyze the reaction of ATP and AMP to form ADP, rely on large scale domain movements to entrain their substrates and exclude waters to form a catalytically competent active site. New methods are under development that can enhance the sampling of configurations to be able to explore the free energy cost for the closure of proteins to test the hypothesis that the ligand free protein actually samples a large conformational space, including conformations that are designed to trap ligands. The figure below is the free energy surface that spans the open to closed conformations of AK. It shows that there is a modest barrier separating open AK from a state that resembles the closed form. Other enzymes under study by combinations of quantum chemistry, molecular dynamics, free energy and docking methods are prostaglandin endoperoxide synthase, dihydroneopterin aldolase and cytosine deaminase.
Selected Publications
Rational Design of Hetero-ring-expanded Guanine Analogs with Enhanced Properties for Modified DNA Building Blocks, J.M. Zhang, R.I. Cukier and Y.X. Bu, J. Phys. Chem. B 2007, 111, 8335-8341.Hamiltonian and Distance Replica Exchange Method Studies of Met-enkephalin, L. Su and R.I. Cukier, J. Phys. Chem. B 2007, 111, 12310-12321
A combined ONIOM Quantum Chemical-Molecular Dynamics Study of Zinc-Uracil Bond Breaking in Yeast Cytosine Deaminase, L.S. Yao, H.G. Yan and R.I. Cukier, J. Phys. Chem. B 2006, 110, 26320-26326.
Molecular Dynamics of Apo-adenylate kinase: A Distance Replica Exchange Method for the Free Energy of Conformational Fluctuations, H.F. Lou and R.I. Cukier, J. Phys. Chem. B 2006, 110, 24121-24137.
Water Chain Formation and Possible Proton Pumping Routes in Rhodobacter Sphaeroides Cytochrome c Oxidase: A Molecular Dynamics Comparison of the Wild Type and R481k Mutant, S.A. Seibold, D.A. Mills, S. Ferguson-Miller and R.I. Cukier, Biochemistry 2005, 44, 10475-10485.
A Molecular Dynamics Study of Water-Chain Formation in the Proton-Conducting K Channel of Cytochrome c Oxidase, R.I. Cukier, Biochim. et Biophys. Acta 2005, 1706, 134-146.
