Speaker: António Baptista – Molecular Simulation Lab
The study of pH-dependent allosteric processes presents a significant challenge, both experimentally and computationally. This presentation illustrates how we can apply theoretical and computational methods to explore an interesting case of allostery involving protein–ligand binding and dimerization. As a model system, we use β-lactoglobulin, a small protein from bovine milk known to dimerize and bind palmitic acid in a hydrophobic pocket ─ both processes sensitive to pH. Ligand binding to the apo and holo forms is analyzed using pH-dependent free energy profiles obtained through the use of constant-pH molecular dynamics simulations and a thermodynamic linkage relation, avoiding the need of performing heavy computational calculations. Dimerization is found to be more favorable near the isoionic point, as observed experimentally. Palmitate binding is found to be more favorable around pH 6–7, a biologically relevant pH range at which the gate covering the binding site is known to open. A pH-dependent measure of allosteric coupling is computed, showing that ligand binding and dimerization exhibit an antagonist relationship within the studied pH range of 3–8, with binding destabilizing dimerization and vice versa.
SCANs are weekly seminars that happen every Wednesday at noon by in-house researchers and invited speakers at ITQB NOVA.
