title: Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
abstract: Molecular recognition is rarely a two-body protein-ligand problem, as it often involves the dynamic interplay of multiple molecules that together control the binding process. Myo-inositol monophosphatase (IMPase), a drug target for bipolar disorder, depends on 3 Mg(2+) ions as cofactor for its catalytic activity. Although the crystallographic pose of the pre-catalytic complex is well characterized, the binding process by which substrate, cofactor and protein cooperate is essentially unknown. Here, we have characterized cofactor and substrate cooperative binding by means of large-scale molecular dynamics. Our study showed the first and second Mg(2+) ions identify the binding pocket with fast kinetics whereas the third ion presents a much higher energy barrier. Substrate binding can occur in cooperation with cofactor, or alone to a binary or ternary cofactor-IMPase complex, although the last scenario occurs several orders of magnitude faster. Our atomic description of the three-body mechanism offers a particularly challenging example of pathway reconstruction, and may prove particularly useful in realistic contexts where water, ions, cofactors or other entities cooperate and modulate the binding process.
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), Doctor Aiguader 88, 08003, Barcelona, Spain.|Acellera, Barcelona Biomedical Research Park, C Dr Aiguader 88, 08003, Barcelona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Ferruz
authors.affiliation: Research Informatics, Janssen Research and Development, Janssen Cilag S A, Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain.
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pineda-Lucena
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), Doctor Aiguader 88, 08003, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain.
authors.forename: Gianni
authors.initials: G
authors.lastname: De Fabritiis
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D002413:Cations, Divalent; D003067:Coenzymes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007294:Inositol / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008274:Magnesium / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D002413:Cations, Divalent; D003067:Coenzymes; D007294:Inositol; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D008274:Magnesium