(Thermo)dynamic role of receptor flexibility, entropy, and motional correlation in protein-ligand binding

The binding of 2-amino-5-methylthiazole to the W191G cavity mutant of cytochrome c peroxidase is on ideal test case to investigate the entropic contribution to the binding free energy due to changes in receptor flexibility. The dynamic and thermodynamic role of receptor flexibility are studied by 50 ns-long explicit-solvent molecular dynamics simulations of three separate receptor ensembles: W191G binding a K+ ion, W191G-2a5mt complex with a closed 190-195 gating loop, and apo with an open loop. We employ a method recently proposed to estimate accurate absolute single-molecule configurational entropies and their differences for systems undergoing conformational transitions. We find that receptor flexibility plays a generally underestimated role in protein-ligand binding (thermo)dynamics and that changes of receptor motional correlation determine such large entropy contributions.