Dynamic Docking of a Medium-Sized Molecule to Its Receptor by Multicanonical MD Simulations

A medium-sized and highly flexible inhibitor to the enzyme β-secretase 1 (BACE), which produces the amyloid β-peptide by cleavage of its precursor protein, was dynamically docked into the large and wide catalytic cleft of BACE that binds to the amyloid-precursor by employing multicanonical molecular dynamics (McMD) simulations. We applied our method to predict the native binding configuration and sample the intermediary structures connecting this natively bound state to the unbound one. Representative structures located at free energy minima obtained from McMD were taken and subjected to canonical simulations to refine and validate them, reproducing the native complex structure in agreement with the experimental data in the most stable structure, i.e., the one at the global minimum. In addition, the binding free energy was estimated by umbrella sampling (US) simulations along representative pathways obtained from the McMD ensemble, followed by weighted histogram analysis to estimate the affinity, which also reproduced the experimental inhibitory affinity. Interestingly, the loss of interactions between the two molecules along the pathway was clearly shown in the free energy landscape, reiterating the fundamental importance of atomistic interactions to the binding affinity between receptor and drug compound. The sampled ensemble by the US simulations smoothly connected the bound and unbound states, refining the binding pathway while staying true to the McMD ensemble.