Temperature Accelerated Sliced Sampling to Probe Ligand Dissociation from Protein

Modelingligand unbinding in proteins to estimate the free energyof binding and probing the mechanism presents several challenges.They primarily pertain to the entropic bottlenecks resulting fromprotein and solvent conformations. While exploring the unbinding processesusing enhanced sampling techniques, very long simulations are requiredto sample all of the conformational states as the system gets trappedin local free energy minima along transverse coordinates. Here, wedemonstrate that temperature accelerated sliced sampling (TASS) isan ideal approach to overcome some of the difficulties faced by conventionalsampling methods in studying ligand unbinding. Using TASS, we studythe unbinding of avibactam inhibitor molecules from the Class C & beta;-lactamase(CBL) active site. Extracting CBL-avibactam unbinding free energetics,unbinding pathways, and identifying critical interactions from theTASS simulations are demonstrated.