Conformational transition in the substrate binding domain of β-secretase exploited by NMA and its implication in inhibitor recognition: BACE1–myricetin a case study

BACE1 is a key protease involved in the proteolysis of amyloid precursor protein (APP) that generates a toxic peptide amyloid beta (Aβ), a pathological feature of Alzheimer's disease (AD). The enzyme is believed to possess an open and a closed conformation that corresponds to its free and inhibitor-bound form respectively. Here, we study the dynamic transition of BACE1 employing normal mode analysis (NMA) using a simplified elastic network model (ENM). Estimation of the catalytic cavity volume on the structures of BACE1 encoded by the lowest frequency normal mode reveals the dynamical transition of the enzyme from the open to the closed conformer. Detailed analysis reveals that concerted movement of different loop segments in the active site of the protein, namely flap regions, 10s loop, A loop and F loop, squeeze the catalytic cavity between the N-terminal and C-terminal lobe of the substrate binding domain of BACE1. We also propose that the NMA encoded multiple receptor conformations (MRC) of BACE1 elucidate the pharmacophoric feature necessary to inhibit the enzyme by a polyphenol, myricetin. van der Waals interaction is found to be the main driving force that guides the ligand induced conformational switching to the closed conformer. We suggest that NMA derived MRC of BACE1 is an efficient way to treat the receptor flexibility in docking and thus can be further applied in virtual screening and structure based drug design.

► Deciphering the functional dynamics of BACE1 from open to closed conformation by using normal mode analysis.
► Atomistic insight into the active site cavity of the protein reveals the mechanism of transition.
► Role of flap and other loops in the dynamic transition of the protein.
► By using NMA encoded multiple receptor conformations (MRC) of BACE1 to successfully model flexibility of receptor in molecular docking of an inhibitor myricetin.
► Elucidate the pharmacophoric feature and mechanism necessary to inhibit the enzyme by myricetin.