β-微管蛋白(TUBB)蛋白是微管细胞骨架的组成部分之一,在中枢神经系统中起着至关重要的作用。TUBB的遗传变异导致皮质发育不良,与轴突引导和神经元迁移有关的发育性大脑缺陷。在这项研究中,我们评估致病变异(Q15K,Y222F,M299V,V353I,和E401K)的TUBB蛋白,并与非致病性变体G235S进行比较,以确定它们对蛋白动力学的影响,从而导致皮质发育不良。在分析的变体中,Q15K,Y222F,M299V,和E401K被发现具有有害作用。然后,对变体结构进行建模,并评估其与已知辅因子鸟苷-5'-三磷酸(GTP)的亲和力,结果显示变体与野生型(-7.428kcal/mol)相比,不同的结合能介于(-7.436至-6.950kcal/mol)之间。最后,对每个变异体的分子动力学模拟进行了研究,结果显示致病性变异体和非致病性变异体的轨迹存在差异.我们的分析表明,TUBB结构的氨基酸残基的变化显着影响蛋白质的柔韧性及其与已知辅因子的相互作用。总的来说,我们的研究结果为TUBB变异体与其结构动力学之间的关系提供了见解,这些结构动力学可能导致导致皮质发育不良的多种效应.
Beta-tubulin (TUBB) protein is one of the components of the microtubule cytoskeleton that plays a critical role in the central nervous system. Genetic variants of TUBB cause cortical dysplasia, a developmental brain defect implicated in axonal guidance and the neuron migration. In this study, we assess pathogenic variants (Q15K, Y222F, M299V, V353I, and E401K) of TUBB protein and compared with non-pathogenic variant G235S to determine their impact on protein dynamic to cause cortical dysplasia. Among the analyzed variants, Q15K, Y222F, M299V, and E401K were noticed to have deleterious effect. Then, variant structures were modeled and their affinity with their known cofactor Guanosine-5\'-triphosphate (GTP) was assessed which showed diverse binding energies ranged between (-7.436 to -6.950 kcal/mol) for the variants compared to wild-type (-7.428 kcal/mol). Finally, the molecular dynamics simulation of each variant was investigated which showed difference in trajectory between the pathogenic and non-pathogenic variant. Our analysis suggests change in amino acid residue of TUBB structure has notably affects the protein flexibility and their interactions with known cofactor. Overall, our findings provide insight on the relationship between TUBB variants and their structural dynamics that may cause diverse effects leading to cortical dysplasia.