Inner cavities and conformational changes modulate ligand uptake in microbial globins

BUSTAMANTE, JUAN PABLO; ABBRUZZETTI, STEFANIA; GAUTO, DIEGO; BOECHI, LEONARDO; BONAMORE, ALESSANDRA; BOFFI, ALBERTO; BRUNO, STEFANO; FEIS, ALESSANDRO; FOGGI, PAOLO; ESTRIN, DARÍO; VIAPPIANI, CRISTIANO

Congreso; 18th International Conference on Oxygen-Binding and Sensing Proteins; 2014

The presence of cavities and tunnels in the interior of proteins, in conjunction with the structural plasticity arising from the coupling to the thermal fluctuations of the protein scaffold, has profound consequences on the shape and the energy barriers encountered by ligands moving through the protein matrix. We review a prototype case for which quantitative analysis of experimental rebinding kinetics from laser flash photolysis and molecular simulations synergistically converge to gain insight into the factors that control the migration mechanisms and the heme affinity for ligands. In the thermostable truncated hemoglobin from Thermobifida fusca (Tf-trHbO) the plasticity of protein structure defines a branched pathway connecting the ligand binding site and the solvent. The presence of a water molecule in the vicinity of the iron heme, stabilized by WG8 with the assistance of YCD1, exerts a steric hindrance for binding of an exogenous ligand. Mutation of these residues decreases the barrier imposed by the water molecules to ligand binding and leads to a dramatic increase in binding rate, which occurs mostly on the subnanosecond time scale.