Avram Speranta, Milac Adina, Mernea Maria, Mihailescu Dan, Putz Mihai V, Buiu Catalin
Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania.
Department of Biology-Chemistry, Faculty of Chemistry, Biology, Geography, West University of Timisoara, 16th Pestalozzi Str., Timisoara 300115, Romania.
Int J Mol Sci. 2014 Nov 18;15(11):21381-400. doi: 10.3390/ijms151121381.
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.
有丝分裂阻滞缺陷蛋白Mad1和Mad2是纺锤体组装检查点的两个组成部分，它们的过表达是染色体不稳定（CIN）的危险因素，也是许多遗传疾病的触发因素。Mad2从无活性的开放构象（O-Mad2）转变为活性的封闭构象（C-Mad2），或者Mad2与特定伴侣（细胞分裂周期蛋白20（Cdc20）或Mad1）的结合，是先前药物基因组学研究的目标。在此，我们预测了Mad2与Cdc20的结合以及Mad2从开放到封闭的相互转化率，并通过将定量构效关系（QSAR）方法扩展到Mad2等大型蛋白质，确定了对这些过程有关键贡献的分子特征。基于23个诱导CIN相关功能变化的Mad2突变体的已发表数据建立了QSAR模型。用于预测Mad2天然和突变体作用机制及其在遗传疾病中的参与情况的最相关描述符是空间（范德华面积和溶剂可及面积及其细分）和能量范德华能量描述符。统计系数的显著值表明了我们QSAR模型的可靠性：交叉验证相关系数q2（0.53 - 0.65）和拟合相关系数r2（0.82 - 0.90）。此外，基于已建立的QSAR方程，我们合理设计并分析了九个全新的Mad2突变体，它们可能是CIN的促进因子。
