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.

§The Persian Gulf Marine Biotechnology Research Center The Persian Gulf Biomedical Sciences Research Institute Bushehr University of Medical Sciences Bushehr Iran

†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

∥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

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