Temperature Accelerated Sliced Sampling to Probe Ligand Dissociation from Protein.

Modeling ligand unbinding in proteins to estimate the free energy of binding and probing the mechanism presents several challenges. They primarily pertain to the entropic bottlenecks resulting from protein and solvent conformations. While exploring the unbinding processes using enhanced sampling techniques, very long simulations are required to sample all of the conformational states as the system gets trapped in local free energy minima along transverse coordinates. Here, we demonstrate that temperature accelerated sliced sampling (TASS) is an ideal approach to overcome some of the difficulties faced by conventional sampling methods in studying ligand unbinding. Using TASS, we study the unbinding of avibactam inhibitor molecules from the Class C β-lactamase (CBL) active site. Extracting CBL-avibactam unbinding free energetics, unbinding pathways, and identifying critical interactions from the TASS simulations are demonstrated.