Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions.

The β-amyloid cleaving enzymes 1 and 2 (BACE1 and BACE2) have been regarded as the prospective targets for clinically treating Alzheimer's disease (AD) in the last two decades. Thus, insight into the binding differences of inhibitors to BACE1 and BACE2 is of significance for designing highly selective inhibitors toward the two proteins. In this work, multiple short molecular dynamics (MSMD) simulations are coupled with the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding selectivity of three inhibitors DBO, CS9, and SC7 on BACE1 over BACE2. The results show that the entropy effect plays a key role in selectivity identification of inhibitors toward BACE1 and BACE2, which determines that DBO has better selectivity toward BACE2 over BACE1, while CS9 and CS7 can more favorably bind to BACE1 than BACE2. The hierarchical clustering analysis based on energetic contributions of residues suggests that BACE1 and BACE2 share the common hot interaction spots. The residue-based free-energy decomposition method was applied to compute the inhibitor-residue interaction spectrum, and the results recognize four common binding subpockets corresponding to the different groups of inhibitors, which can be used as efficient targets for designing highly selective inhibitors toward BACE1 and BACE2. Therefore, these results provide a useful molecular basis and dynamics information for development of highly selective inhibitors targeting BACE1 and BACE2.