title: Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.
abstract: Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding to specific partners (cell-division cycle protein 20 (Cdc20) or Mad1) were targets of previous pharmacogenomics studies. Here, Mad2 binding to Cdc20 and the interconversion rate from open to closed Mad2 were predicted and the molecular features with a critical contribution to these processes were determined by extending the quantitative structure-activity relationship (QSAR) method to large-size proteins such as Mad2. QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes. The most relevant descriptors identified for predicting Mad2 native and mutants action mechanism and their involvement in genetic disorders are the steric (van der Waals area and solvent accessible area and their subdivided) and energetic van der Waals energy descriptors. The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53-0.65) and fitted correlation r2 (0.82-0.90). Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.
authors.affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. speranta.avram@gmail.com.
authors.forename: Speranta
authors.initials: S
authors.lastname: Avram
authors.affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. amilac@biochim.ro.
authors.forename: Adina
authors.initials: A
authors.lastname: Milac
authors.affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. maria.mernea@bio.unibuc.ro.
authors.forename: Maria
authors.initials: M
authors.lastname: Mernea
authors.affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. dan.mihailescu@bio.unibuc.ro.
authors.forename: Dan
authors.initials: D
authors.lastname: Mihailescu
authors.affiliation: Department of Biology-Chemistry, Faculty of Chemistry, Biology, Geography, West University of Timisoara, 16th Pestalozzi Str., Timisoara 300115, Romania. mv_putz@yahoo.com.
authors.forename: Mihai V
authors.initials: MV
authors.lastname: Putz
authors.affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. catalin.buiu@acse.pub.ro.
authors.forename: Catalin
authors.initials: C
authors.lastname: Buiu
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D064199:Cdc20 Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D064246:Mad2 Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021281:Quantitative Structure-Activity Relationship
chemical_list: D064199:Cdc20 Proteins; D064246:Mad2 Proteins