Recent experimental and theoretical studies have focused on the mechanism of the A-cluster active site of acetyl-CoA synthase that produces acetyl-CoA from a methyl group, carbon monoxide, and CoA. Several proposals have been made concerning the redox states of the (Ni-Ni) bimetallic center and the iron-sulfur cluster connected to one of the metals. Using hybrid density functional theory, we have investigated putative intermediate states from the catalytic cycle. Among our conclusions are the following: (i) the zerovalent state proposed for the proximal metal is unlikely if the charge on the iron-sulfur cluster is +2; (ii) a mononuclear mechanism in which both CO and CH3 bind the proximal nickel is favored over the binuclear mechanism in which CO and CH3 bind the proximal and distal nickel ions, respectively; (iii) the formation of a disulfide bond in the active site could provide the two electrons necessary for the reaction but only if methylation occurs simultaneously; and (iv) the crystallographic closed form of the active site needs to open to accommodate ligands in the equatorial site.