Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations.

The β-amyloid cleaving enzyme 1 (BACE1) has been thought to be an efficient target for treatment of Alzheimer's disease (AD). Deep insight into inhibitor-BACE1 binding mechanism is of significance for design of potent drugs toward BACE1. In this work, multiple replica accelerated molecular dynamics (MR-aMD) simulations, principal component (PC) analysis, and free energy landscapes were integrated to decode the effect of disulfide bonds (SSBs) in BACE1 on bindings of three inhibitors 3KO, 3KT, and 779 to BACE1. The results from cross-correlation analysis suggest that the breaking of SSBs exerts significant influence on structural flexibility and internal dynamics of inhibitor-bound BACE1. PC analysis and free energy landscapes reveal that the breaking of SSBs not only evidently induces the conformational rearrangement of BACE1 but also highly changes binding poses of three inhibitors in BACE1 and leads to more disordered binding of three inhibitors to BACE1, which is further supported by the increase in binding entropy of inhibitors to BACE1 due to the breaking of SSBs. Residue-based free energy decomposition method was utilized to evaluate contributions of separate residues to inhibitor-BACE1 binding. The results suggest that although the breaking of SSBs in BACE1 does not destroy the interaction network of inhibitors with BACE1 it changes interaction strength of some residues with inhibitors. Meanwhile, the information from residue-based free energy decomposition indicates that residues L91, S96, V130, Y132, Q134, W137, F169, I171, and I179 can be used as efficient targets of drug design toward BACE1.