title: Molecular dynamics characterization of five pathogenic Factor X mutants associated with decreased catalytic activity.
abstract: Factor X (FX) is one of the major players in the blood coagulation cascade. Upon activation to FXa, it converts prothrombin to thrombin, which in turn converts fibrinogen into fibrin (blood clots). FXa deficiency causes hemostasis defects, such as intracranial bleeding, hemathrosis, and gastrointestinal blood loss. Herein, we have analyzed a pool of pathogenic mutations, located in the FXa catalytic domain and directly associated with defects in enzyme catalytic activity. Using chymotrypsinogen numbering, they correspond to D102N, T135M, V160A, G184S, and G197D. Molecular dynamics simulations were performed for 1.68 μs on the wild-type and mutated forms of FXa. Overall, our analysis shows that four of the five mutants considered, D102N, T135M, V160A, and G184S, have rigidities higher than those of the wild type, in terms of both overall protein motion and, specifically, subpocket S4 flexibility, while S1 is rather insensitive to the mutation. This acquired rigidity can clearly impact the substrate recognition of the mutants.
authors.affiliation: Kaust Catalysis Center, King Abdullah University of Science and Technology , Thuwal 23955-6900, Saudi Arabia.
authors.forename: Safwat
authors.initials: S
authors.lastname: Abdel-Azeim
authors.forename: Romina
authors.initials: R
authors.lastname: Oliva
authors.forename: Edrisse
authors.initials: E
authors.lastname: Chermak
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Luigi
authors.initials: L
authors.lastname: Cavallo
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D005170:Factor X / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D025341:Principal Component Analysis; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D005170:Factor X