人类基因非同义单核苷酸多态性的计算机结构与功能分析
In-silico structural and functional analysis of nonsynonymous single nucleotide polymorphisms in human gene.
作者信息
Tondar Abtin, Irfan Muhammad, Sánchez-Herrero Sergio, Athar Hafsa, Haqqi Aleena, Bepari Asim Kumar, Liñán Laura Calvet, Hervás Marin David
机构信息
Department of Computer Science, Multimedia and Telecommunication, Interuniversity Doctoral Program in Bioinformatics, Universitat Oberta de Catalunya, Barcelona (UOC), Spain.
Stanford Deep Data Research Center, Stanford University, Stanford, USA.
出版信息
In Silico Pharmacol. 2025 Feb 25;13(1):32. doi: 10.1007/s40203-025-00319-3. eCollection 2025.
UNLABELLED
Non-synonymous single nucleotide polymorphisms (nsSNPs), also known as missense SNPs, can seriously affect an individual's vulnerability to numerous diseases, including cancer. In this study, we conducted a comprehensive in-silico analysis to examine the structural and functional implications of nsSNPs within the Folate Hydrolase 1() gene, which encodes the Prostate-Specific Membrane Antigen (PSMA). A total of 504 SNPs were retrieved, and after filtering, 15 pathogenic nsSNPs were identified using five different in-silico tools. Three of these SNPs-R255H (rs375565491), R255C (rs201789325), and G168E (rs267602926)-were consistently predicted to be pathogenic across all in-silico tools. MutPred2 was used to predict the structural and functional consequences of the identified mutations. The analysis revealed multiple alterations in the PSMA protein, including changes in helical conformations, glycosylation patterns, transmembrane properties, and solvent accessibility. Furthermore, I-Mutant 2.0 analysis demonstrated a decrease in protein stability for most nsSNPs, except for rs267602926 (G168E), which was predicted to increase stability. Conservation analysis using ConSurf revealed varying degrees of amino acid conservation, with R255H and R255C identified as highly conserved residues, indicating their potential functional and structural significance. Additionally, post-translational modification (PTM) analysis indicated that while phosphorylation and methylation sites remained unchanged, specific glycosylation sites were lost in two pathogenic mutant variants (R255H and R255C), potentially affecting PSMA function and adversely impacting prostate cancer. Our findings highlight the importance of in silico studies to investigate the structural and functional impacts of nsSNPs on the PSMA protein. Such in silico studies can deepen our understanding of the roles of nsSNPs in prostate cancer onset, progression, and drug resistance.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40203-025-00319-3.
未标注
非同义单核苷酸多态性（nsSNPs），也称为错义单核苷酸多态性，可严重影响个体对包括癌症在内的多种疾病的易感性。在本研究中，我们进行了全面的计算机模拟分析，以研究叶酸水解酶1（）基因内nsSNPs的结构和功能影响，该基因编码前列腺特异性膜抗原（PSMA）。共检索到504个单核苷酸多态性，经过筛选，使用五种不同的计算机模拟工具鉴定出15个致病性nsSNPs。其中三个单核苷酸多态性——R255H（rs375565491）、R255C（rs201789325）和G168E（rs267602926）——在所有计算机模拟工具中均被一致预测为致病性。使用MutPred2预测已鉴定突变的结构和功能后果。分析揭示了PSMA蛋白的多种改变，包括螺旋构象、糖基化模式、跨膜特性和溶剂可及性的变化。此外，I-Mutant 2.0分析表明，除rs267602926（G168E）预计会增加稳定性外，大多数nsSNPs的蛋白质稳定性降低。使用ConSurf进行的保守性分析揭示了不同程度的氨基酸保守性，R255H和R255C被鉴定为高度保守的残基，表明它们潜在的功能和结构重要性。此外，翻译后修饰（PTM）分析表明，虽然磷酸化和甲基化位点保持不变，但两个致病性突变变体（R255H和R255C）中特定的糖基化位点丢失，可能影响PSMA功能并对前列腺癌产生不利影响。我们的研究结果强调了计算机模拟研究对于探究nsSNPs对PSMA蛋白的结构和功能影响的重要性。此类计算机模拟研究可加深我们对nsSNPs在前列腺癌发生、发展和耐药性中作用的理解。
补充信息
在线版本包含可在10.1007/s40203-025-00319-3获取的补充材料。
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