Small ligand interactions with hemoglobins: from ligand migration to reactivity studied by computer simulations

LUCIANA CAPECE

Montevideo

Congreso; XLVI International Congress of Theoretical Chemists of Latin Expression; 2023

The globin superfamily is formed by a widely distributed group of heme proteins, which are responsible for a variety of biological functions in all kingdoms of life. Many of these functions involve the coordination of small ligands to the prosthetic heme group, a process that is tightly controlled. The iron in the heme group is coordinated to the four equatorial porphyrin nitrogen atoms and axially coordinated by the absolutely conserved proximal histidine F8 (HisF8), leading to the characteristic pentacoordinated (5c) state. The vacant coordination at the distal site permits the binding of diatomic ligands (as molecular oxygen, among others) and allows the protein to fulfill its function. This process involves ligand migration from the protein exterior towards the distal site, and ligand binding to the heme iron (which in some cases involves the cleavege of a pre-existence bond in the distal cavity) In several globins, the distal site is blocked by the coordination of an endogenous residue, usually the distal histidine (HisE7), thus resulting in a bis-histidyl hexacoordinated (6c) species. Other regulatory mechanisms as allosterism are also present in the globin family, as is the case of tetrameric hemoglobin.In the last two decades, in our group we studied a wide spectrum of globins from different organisms. We focus our attention in ligand affinity, reactivity, ligand migration, and conformational changes. For that purpose, we applied and also developed different models and methods, ranging from QM/MM calculations, advanced sampling techniques in the context of classical molecular dynamics simulations, and coarse grain models. In this context, I will show some selected examples where simulations combined with experimental information allowed us to understand the molecular basis of these different proceses and also shed light on common mechanisms that are present throughout the globin family.