Department of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
Eat Weight Disord. 2023 Nov 21;28(1):97. doi: 10.1007/s40519-023-01618-4.
Anorexia nervosa (AN) is a neuropsychological public health concern with a socially disabling routine and affects a person's healthy relationship with food. The role of the NNAT (Neuronatin) gene in AN is well established. The impact of mutation at the protein's post-translational modification (PTM) site has been exclusively associated with the worsening of the protein's biochemical dynamics.
To understand the relationship between genotype and phenotype, it is essential to investigate the appropriate molecular stability of protein required for proper biological functioning. In this regard, we investigated the PTM-acetylation site of the NNAT gene in terms of 19 other specific amino acid probabilities in place of wild type (WT) through various in silico algorithms. Based on the highest pathogenic impact computed through the consensus classifier tool, we generated 3 residue-specific (K59D, P, W) structurally modified 3D models of NNAT. These models were further tested through the AutoDock Vina tool to compute the molecular drug binding affinities and inhibition constant (Ki) of structural variants and WT 3D models.
With trained in silico machine learning algorithms and consensus classifier; the three structural modifications (K59D, P, W), which were also the most deleterious substitution at the acetylation site of the NNAT gene, showed the highest structural destabilization and decreased molecular flexibility. The validation and quality assessment of the 3D model of these structural modifications and WT were performed. They were further docked with drugs used to manage AN, it was found that the ΔGbind (kcal/mol) values and the inhibition constants (Ki) were relatively lower in structurally modified models as compared to WT.
We concluded that any future structural variation(s) at the PTM-acetylation site of the NNAT gene due to possible mutational consequences, will serve as a basis to explore its relationship with the propensity of developing AN.
No level of evidence-open access bioinformatics research.
神经性厌食症（AN）是一种神经心理学公共卫生问题，具有社交致残的日常行为，影响个人与食物的健康关系。神经元蛋白（NNAT）基因在 AN 中的作用已得到充分证实。蛋白质翻译后修饰（PTM）位点突变的影响仅与蛋白质生化动力学的恶化有关。
为了了解基因型与表型之间的关系，研究蛋白质的适当分子稳定性对于正确的生物功能至关重要。在这方面，我们通过各种计算算法，研究了 NNAT 基因的 PTM-乙酰化位点，研究了 19 个其他特定氨基酸概率代替野生型（WT）的情况。根据共识分类器工具计算的最高致病性影响，我们生成了 3 个具有特定残基（K59D、P、W）的 NNAT 结构修饰 3D 模型。通过 AutoDock Vina 工具进一步测试这些模型，以计算结构变体和 WT 3D 模型的分子药物结合亲和力和抑制常数（Ki）。
使用经过训练的计算机器学习算法和共识分类器；在 NNAT 基因的乙酰化位点最具破坏性的三种结构修饰（K59D、P、W），显示出最高的结构不稳定性和降低的分子灵活性。对这些结构修饰和 WT 的 3D 模型进行了验证和质量评估。进一步用用于治疗 AN 的药物对它们进行对接，发现结构修饰模型的ΔGbind（kcal/mol）值和抑制常数（Ki）相对低于 WT。
我们得出结论，由于可能的突变后果，NNAT 基因 PTM-乙酰化位点的任何未来结构变异都将成为探索其与发生 AN 倾向关系的基础。
无证据水平-开放获取生物信息学研究。
