Abuelrub Anwar, Erol Ismail, Nalbant Bingol Nurdeniz, Ozemri Sag Sebnem, Temel Sehime G, Durdağı Serdar
Laboratory for Innovative Drugs (Lab4IND), Computational Drug Design Center (HITMER), Bahçeşehir University, 34734 İstanbul, Türkiye.
Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahçeşehir University, 34734 Istanbul, Türkiye.
ACS Chem Neurosci. 2025 Jan 10. doi: 10.1021/acschemneuro.4c00570.
is implicated in a range of conditions, including autism spectrum disorder, intellectual disability, seizures, autosomal recessive nonsyndromic intellectual disability, heterotaxy, and ciliary dysfunction. In order to understand the molecular mechanisms underlying these conditions, we focused on the structural and dynamic activity consequences of mutations within this gene. In this study, whole exome sequencing identified the c.1552G > A (GLU518LYS) missense mutation in the in an 18-year-old male, linking it to intellectual disability and autism. In addition to the GLU518LYS mutation, we conducted a comprehensive analysis of other predefined missense mutations (i.e., PRO192LEU, GLN506ARG, PRO532LEU, GLY781VAL, and GLY781GLU) found within the . Utilizing all-atom molecular dynamics (MD) simulations and neighborhood interaction analyses, we delve into the impact of these mutations on protein structure and function at an atomic level, aiming to shed light on their contribution to the pathogenesis of related diseases. The results suggest that GLU518LYS, GLY781VAL, and GLY781GLU mutations did not significantly alter overall global protein structure compared to the wild type, while PRO192LEU, GLN506ARG, and PRO532LEU exhibited slightly higher protein root-mean-square deviation (RMSD) values, which may indicate potential impacts on whole protein stability. Moreover, neighborhood interaction analysis indicated that ASP85 emerges as a unique interaction partner specifically associated with the GLU518LYS mutation, whereas LYS75, which interacts with the ASP85 in the mutated form, is absent in the wild type. This alteration signifies a crucial reconfiguration in the local interaction network at the site of the mutation.
它与一系列病症有关，包括自闭症谱系障碍、智力残疾、癫痫、常染色体隐性非综合征性智力残疾、内脏异位和纤毛功能障碍。为了了解这些病症背后的分子机制，我们聚焦于该基因内突变的结构和动态活性后果。在本研究中，全外显子组测序在一名18岁男性中鉴定出该基因的c.1552G > A（GLU518LYS）错义突变，将其与智力残疾和自闭症联系起来。除了GLU518LYS突变外，我们还对该基因内发现的其他预定义错义突变（即PRO192LEU、GLN506ARG、PRO532LEU、GLY781VAL和GLY781GLU）进行了全面分析。利用全原子分子动力学（MD）模拟和邻域相互作用分析，我们在原子水平上深入研究这些突变对蛋白质结构和功能的影响，旨在阐明它们对相关疾病发病机制的贡献。结果表明，与野生型相比，GLU518LYS、GLY781VAL和GLY781GLU突变并未显著改变蛋白质的整体全局结构，而PRO192LEU、GLN506ARG和PRO532LEU的蛋白质均方根偏差（RMSD）值略高，这可能表明对整个蛋白质稳定性有潜在影响。此外，邻域相互作用分析表明，ASP85成为与GLU518LYS突变特异性相关的独特相互作用伙伴，而在野生型中不存在与突变形式的ASP85相互作用的LYS75。这种改变表明突变位点处局部相互作用网络发生了关键的重新配置。
