title: Taming molecular flexibility to tackle rare diseases.
abstract: Many mutations responsible of Fabry disease destabilize lysosomal alpha-galactosidase, but retain the enzymatic activity. These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis. We demonstrate the effectiveness of molecular dynamics simulations to correlate the genotype to the severity of the disease. We studied the relation between protein flexibility and residual enzymatic activity of pathological missense mutants in the cell. We found that mutations occurring at flexible sites are likely to retain activity in vivo. The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases.
authors.affiliation: Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy. Electronic address: cubellis@unina.it.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.affiliation: Laboratoire de Biochimie Théorique, CNRS, UPR9080, Univ Paris Diderot, Sorbonne Paris Cité, 13 rue Pierre et Marie Curie, 75005 Paris, France. Electronic address: baaden@smplinux.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Baaden
authors.affiliation: Istituto di Chimica Biomolecolare-CNR, 80078 Pozzuoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Andreotti
mesh_terms: D000795:Fabry Disease / Q000201:enzymology / Q000235:genetics; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D000519:alpha-Galactosidase / Q000737:chemistry / Q000235:genetics
chemical_list: D000519:alpha-Galactosidase
keywords: Diagnostic use; Disease; Molecular dynamics; Protein stability
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