Evidence of a Thermodynamic Ramp for Hole Hopping to Protect a Redox Enzyme from Oxidative Damage.

Redox proteins and enzymes are at risk of irreversible oxidative damage from highly oxidizing intermediates generated in the active site in the case of unsuccessful functional reaction. Chains of tyrosine and/or tryptophan residues have been recently proposed to provide protection to the active site and the whole protein by delivering oxidizing equivalents (holes) out of the protein via a multistep hopping mechanism. In the present work we use a hybrid quantum/classical theoretical-computational methodology based on the perturbed matrix method and on molecular dynamics simulations to calculate the oxidation potential difference along a chain of tyrosine and tryptophan residues in a human redox enzyme of major importance, a superoxide dismutase, which acts as antioxidant defense. We show that the hole hopping is thermodynamically favored along such a chain and that the hopping propensity is strongly affected by the protein environment and in particular by the active site and its second coordination sphere.