Mechanism of the highly effective peptide bond hydrolysis by MOF-808 catalyst under biologically relevant conditions.

Efficient and selective hydrolysis of inert peptide bonds is of paramount importance. MOF-808, a metal-organic framework based on Zr-6 nodes, can hydrolyze peptide bonds efficiently under biologically relevant conditions. However, the details of the catalyst structure and of the underlying catalytic reaction mechanism are challenging to establish. By means of DFT calculations we first investigate the speciation of the Zr-6 nodes and identify the nature of ligands that bind to the Zr6O8H4-x core in aqueous conditions. The core is predicted to strongly prefer a Zr6O8H4 protonation state and to be predominantly decorated by bridging formate ligands, giving Zr-6(mu(3)-O)(4)(mu(3)-OH)(4)(BTC)(2)(HCOO)(6) and Zr-6(mu(3)-O)(4)(mu(3)-OH)(4)(BTC)(2)(HCOO)(5)(OH)(H2O) as the most favorable structures at physiological pH. The GlyGly peptide can bind MOF in several different ways, with the preferred structure involving coordination through the terminal carboxylate analogously to the binding mode of formate ligand. The pre-reactive binding mode in which the amide carbonyl oxygen coordinates the metal core lies 7 kcal higher in free energy. The preferred reaction pathway is predicted to have two close-lying transition states, either of which could be the rate-determining step: nucleophilic attack on the amide carbon atom and C-N bond breaking, with calculated relative free energies of 31 and 32 kcal mol(-1), respectively. Replacement of formate by water and hydroxide at the Zr-6 node is predicted to be possible, but does not appear to play a role in the hydrolysis mechanism.