Mechanistic aspects of the binding of acid–base ligands to ferric heme proteins

MESSIAS, ANDRESA; CARLLINNI COLOMBO, MELISA; PALERMO, JUAN CRUZ; CÓRDOVA, JONATHAN A.; DE SIMONE, GIOVANNA; ASCENZI, PAOLO; ESTRIN, DARÍO A.; CAPECE, LUCIANA; BARI, SARA E.

Biophysical Reviews

Springer

Año: 2025

1867-2450

The kinetics of ligand binding to ferric heme proteins is relevant in a variety of biochemical processes. With a few exceptions,ferric heme proteins at physiological pH typically show the sixth (distal) coordination position of the heme iron occupied bya water molecule. This contrasts with ferrous heme proteins, where this position is usually vacant in the absence of externalligands. In this review, we shed light on mechanistic aspects of this process, by discussing our recent results of binding ofhydrogen sulfide and hydrosulfide ­(H 2 S/HS – ) and disulfane and hydrodisulfide (HSSH/HSS – ) to ferric microperoxidase 11(MP11Fe III ) and metmyoglobin ­(MbFe III ), as well as binding of peroxynitrous acid/peroxynitrite (ONOOH/ONOO – ) to ferricM. tuberculosis nitrobindin ­(NbFe III ). Stopped flow experimental results of ligand binding rates as a function of pH can beanalyzed with a mechanistic proposal consisting of ligand migration and ligand binding steps. Ligand migration to the activesite was studied by using steered classical molecular dynamics simulations. The process of ligand binding substitution of thecoordinated water molecule has been studied using hybrid quantum–classical (QM-MM) tools. Our results suggest that watermolecule release is the critical event of the process in most of the cases, consistently with previous proposals. However, thescenario is complex, since water release depends subtly on the heme environment and may be also assisted by the acid–basebehavior of the incoming ligands. Ligand migration may also play a key role in cases in which the active site entrance is hindered.