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Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

Avram S, Milac A, Mernea M, Mihailescu D, Putz MV, Buiu C - Int J Mol Sci (2014)

Bottom Line: QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes.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 Article: PubMed Central - PubMed

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.

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.

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(a) Correlation between experimental and predicted binding of Mad2 native and mutants (pKdCdc20) obtained by QSAR model 2 (q2 = 0.65, r2 = 0.83); and (b) correlation between experimental and predicted conversion rate of Mad2 native and mutants (pCR) obtained by QSAR model 3 (q2 = 0.60, r2 = 0.90). Black dots correspond to molecules in the training set and white (open) dots to molecules in the test set.
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ijms-15-21381-f001: (a) Correlation between experimental and predicted binding of Mad2 native and mutants (pKdCdc20) obtained by QSAR model 2 (q2 = 0.65, r2 = 0.83); and (b) correlation between experimental and predicted conversion rate of Mad2 native and mutants (pCR) obtained by QSAR model 3 (q2 = 0.60, r2 = 0.90). Black dots correspond to molecules in the training set and white (open) dots to molecules in the test set.

Mentions: Data shown in Table 2 is supported by the appropriate correlations between experimental and predicted binding of Mad2 native and mutants to Cdc20 (pKdCdc20 of Mad2) when van der Waals energy, subdivided van der Waals and water accessible surface areas induced by hydrophobic atoms and count of rigid and rotatable bonds descriptors (QSAR model 2) were simultaneously considered (Figure 1a). The good quality of our statistical parameters q2 and r2 is supported by a reasonable distribution of scatter in Figure 1a.


Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

Avram S, Milac A, Mernea M, Mihailescu D, Putz MV, Buiu C - Int J Mol Sci (2014)

(a) Correlation between experimental and predicted binding of Mad2 native and mutants (pKdCdc20) obtained by QSAR model 2 (q2 = 0.65, r2 = 0.83); and (b) correlation between experimental and predicted conversion rate of Mad2 native and mutants (pCR) obtained by QSAR model 3 (q2 = 0.60, r2 = 0.90). Black dots correspond to molecules in the training set and white (open) dots to molecules in the test set.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264231&req=5

ijms-15-21381-f001: (a) Correlation between experimental and predicted binding of Mad2 native and mutants (pKdCdc20) obtained by QSAR model 2 (q2 = 0.65, r2 = 0.83); and (b) correlation between experimental and predicted conversion rate of Mad2 native and mutants (pCR) obtained by QSAR model 3 (q2 = 0.60, r2 = 0.90). Black dots correspond to molecules in the training set and white (open) dots to molecules in the test set.
Mentions: Data shown in Table 2 is supported by the appropriate correlations between experimental and predicted binding of Mad2 native and mutants to Cdc20 (pKdCdc20 of Mad2) when van der Waals energy, subdivided van der Waals and water accessible surface areas induced by hydrophobic atoms and count of rigid and rotatable bonds descriptors (QSAR model 2) were simultaneously considered (Figure 1a). The good quality of our statistical parameters q2 and r2 is supported by a reasonable distribution of scatter in Figure 1a.

Bottom Line: QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes.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 Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus