Application of the Movable Type Free Energy Method to the Caspase-Inhibitor BindingAffinity Study.

Many studies have provided evidence suggesting that caspases not only contribute to the neurodegeneration associated with Alzheimer's disease (AD) but also play essential roles in promoting the underlying pathology of this disease. Studies regarding the caspase inhibition draw researchers' attention through time due to its therapeutic value in the treatment of AD. In this work, we apply the "Movable Type" (MT) free energy method, a Monte Carlo sampling method extrapolating the binding free energy by simulating the partition functions for both free-state and bound-state protein and ligand configurations, to the caspase-inhibitor binding affinity study. Two test benchmarks are introduced to examine the robustness and sensitivity of the MT method concerning the caspase inhibition complexing. The first benchmark employs a large-scale test set including more than a hundred active inhibitors binding to caspase-3. The second benchmark includes several smaller test sets studying the relative binding free energy differences for minor structural changes at the caspase-inhibitor interaction interfaces. Calculation results show that the RMS errors for all test sets are below 1.5 kcal/mol compared to the experimental binding affinity values, demonstrating good performance in simulating the caspase-inhibitor complexing. For better understanding the protein-ligand interaction mechanism, we then take a closer look at the global minimum binding modes and free-state ligand conformations to study two pairs of caspase-inhibitor complexes with (1) different caspase targets binding to the same inhibitor, and (2) different polypeptide inhibitors targeting the same caspase target. By comparing the contact maps at the binding site of different complexes, we revealed how small structural changes affect the caspase-inhibitor interaction energies. Overall, this work provides a new free energy approach for studying the caspase inhibition, with structural insight revealed for both free-state and bound-state molecular configurations.