title: Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite.
abstract: A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray diffraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding energetics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity.
authors.affiliation: a Área de Química General e Inorgánica, Universidad Nacional de San Luis (UNSL) , Chacabuco 917, San Luis , D5700BWS , Argentina .
authors.forename: Lucas Joel
authors.initials: LJ
authors.lastname: Gutiérrez
authors.forename: Sebastián Antonio
authors.initials: SA
authors.lastname: Andujar
authors.forename: Ricardo Daniel
authors.initials: RD
authors.lastname: Enriz
authors.forename: Héctor Armando
authors.initials: HA
authors.lastname: Baldoni
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000276:immunology*; D016282:Aspartic Acid Endopeptidases / Q000276:immunology*; D000939:Epitopes; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed
chemical_list: D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer; BACE1; allosteric control; immune complex; molecular dynamics simulation