title: Conformational transition in the substrate binding domain of β-secretase exploited by NMA and its implication in inhibitor recognition: BACE1-myricetin a case study.
abstract: 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.
authors.affiliation: Saroj Mohan Institute of Technology, Guptipara, Hooghly, Pin 712512, India.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.forename: Soumalee
authors.initials: S
authors.lastname: Basu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002384:Catalysis; D018360:Crystallography, X-Ray; D004548:Elasticity; D005419:Flavonoids / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D005419:Flavonoids; D008024:Ligands; D011480:Protease Inhibitors; C040015:myricetin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human