title: Catalytic Cycle of Multicopper Oxidases Studied by Combined Quantum- and Molecular-Mechanical Free-Energy Perturbation Methods.
abstract: We have used combined quantum mechanical and molecular mechanical free-energy perturbation methods in combination with explicit solvent simulations to study the reaction mechanism of the multicopper oxidases, in particular, the regeneration of the reduced state from the native intermediate. For 52 putative states of the trinuclear copper cluster, differing in the oxidation states of the copper ions and the protonation states of water- and O2-derived ligands, we have studied redox potentials, acidity constants, isomerization reactions, as well as water- and O2 binding reactions. Thereby, we can propose a full reaction mechanism of the multicopper oxidases with atomic detail. We also show that the two copper sites in the protein communicate so that redox potentials and acidity constants of one site are affected by up to 0.2 V or 3 pKa units by a change in the oxidation state of the other site.
authors.affiliation: †Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, SE-221 00 Lund, Sweden.|‡Institute of Theoretical Chemistry, Jilin University, Changchun 130023, People's Republic of China.
authors.forename: Jilai
authors.initials: J
authors.lastname: Li
authors.affiliation: †Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, SE-221 00 Lund, Sweden.|§The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Farrokhnia
authors.affiliation: ∥Institute of Organic Chemistry and Biochemistry, Gilead Sciences and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic.
authors.forename: Lubomír
authors.initials: L
authors.lastname: Rulíšek
authors.affiliation: †Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, SE-221 00 Lund, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
mesh_terms: D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D004579:Electron Transport; D007536:Isomerism; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D011522:Protons; D012997:Solvents; D014867:Water / Q000737:chemistry
chemical_list: D011522:Protons; D012997:Solvents; D014867:Water; D003300:Copper; D010088:Oxidoreductases; C024748:copper oxidase