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Int. J. Mol. Sci. 2014, 15(11), 21381-21400; doi:10.3390/ijms151121381

Structure–Biological Function Relationship Extended to Mitotic Arrest-Deficient 2-Like Protein Mad2 Native and Mutants-New Opportunity for Genetic Disorder Control

1
Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania
2
Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy Bucharest (IBAR), 296 Spl. Independentei, Bucharest 060031, Romania
3
Department of Biology-Chemistry, Faculty of Chemistry, Biology, Geography, West University of Timisoara, 16th Pestalozzi Str., Timisoara 300115, Romania
4
Department of Automatic Control and Systems Engineering, Politehnica University of Bucharest, 313 Spl. Independentei, Bucharest 060042, Romania
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 29 September 2014 / Revised: 7 November 2014 / Accepted: 7 November 2014 / Published: 18 November 2014
(This article belongs to the Special Issue Chemical Bond and Bonding 2015)
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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. View Full-Text
Keywords: chromosomal instability prediction; mitotic arrest-deficient protein Mad2; computational mutagenesis; quantitative structure-activity relationship (QSAR) chromosomal instability prediction; mitotic arrest-deficient protein Mad2; computational mutagenesis; quantitative structure-activity relationship (QSAR)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Avram, S.; Milac, A.; Mernea, M.; Mihailescu, D.; Putz, M.V.; Buiu, C. Structure–Biological Function Relationship Extended to Mitotic Arrest-Deficient 2-Like Protein Mad2 Native and Mutants-New Opportunity for Genetic Disorder Control. Int. J. Mol. Sci. 2014, 15, 21381-21400.

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