Obtaining Binding Free Energy from a Path Sampling without Force Bias

Binding/dissociation free energy is among the most important quantities for computer-aided drug design. During generating dissociation pathways, the use of force bias can lead to the production of unnatural pathways, which may not sample more plausible dissociation configurations of protein/ligand complexes. Therefore, we apply the Parallel Cascade Selection Molecular Dynamics (PaCS-MD) [J. Chem. Phys. 139, 035103 (2013)] to generate multiple dissociation pathways without applying force biases and specific targeting scheme. We perform dissociation simulation for Hen-egg Lysozyme and a ligand Tri-N-Acetylchitotiose as a test case. Applying Umbrella Sampling (US) for the selected PaCS-MD snapshots, the obtained free energy profile is in good agreement with experimental binding free energy. In addition, from the trajectories of PaCS-MD, we build the Markov State Model and calculate the free energy profile. Without any further simulations as in US, the difference of free energy of the bound state and un-bound state is also well-reproduced.