Implications of seven NTCP mutations for receptor stability and Hepatitis B Virus infectivity: A computational analysis

IF 2.4 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-07-01 Epub Date: 2025-11-20 DOI:10.1016/j.mrfmmm.2025.111921

Amina Kardoudi , Salaheddine Redouane , Salma Madihi , Thomas Jackson , Abdelouaheb Benani

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Abstract

Hepatitis B is a widespread viral infection and a major global public health concern. The human sodium taurocholate co-transporter polypeptide (NTCP) serves as a key receptor for the hepatitis B virus (HBV), enabling its entry into hepatocytes. Understanding how specific NTCP mutations influence its stability and interaction with HBV is critical for elucidating mechanisms of viral infectivity and resistance. This study evaluates the impact of seven non-synonymous NTCP mutations on receptor stability and HBV binding using a comprehensive bioinformatics approach. Mutant NTCP/HBsAg complexes were generated via HADDOCK, and binding affinities were predicted using PRODIGY. Molecular dynamics simulations with GROMACS further assessed the stability and behavior of NTCP/PreS1 complexes. Our findings reveal that V160M and S267F significantly reduce complex stability and binding affinity, suggesting a potential role in natural resistance to HBV infection. Mutations I88T and R84W moderately affect NTCP–HBV interactions, while V200M, I223T, and I279T show minimal impact, maintaining wild-type reference complex characteristics. This study highlights the differential effects of NTCP mutations on HBV infectivity, providing insights into host susceptibility and resistance. The integrative computational strategy offers a robust framework for understanding HBV-host interactions and may aid in identifying novel therapeutic targets.

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7种NTCP突变对受体稳定性和乙型肝炎病毒传染性的影响：计算分析。

乙型肝炎是一种广泛的病毒感染，也是一个主要的全球公共卫生问题。人牛磺酸胆酸钠共转运蛋白多肽（NTCP）是乙型肝炎病毒（HBV）的关键受体，使其能够进入肝细胞。了解特异性NTCP突变如何影响其稳定性和与HBV的相互作用，对于阐明病毒感染和耐药机制至关重要。本研究利用综合生物信息学方法评估了七种非同义NTCP突变对受体稳定性和HBV结合的影响。通过HADDOCK产生突变的NTCP/HBsAg复合物，并用PRODIGY预测其结合亲和力。利用GROMACS进行分子动力学模拟，进一步评估了NTCP/PreS1复合物的稳定性和行为。我们的研究结果表明，V160M和S267F显著降低了复合物的稳定性和结合亲和力，提示在HBV感染的自然抗性中发挥潜在作用。突变I88T和R84W中度影响NTCP-HBV相互作用，而v2m、I223T和I279T影响最小，保持野生型参考复合物特征。这项研究强调了NTCP突变对HBV感染性的不同影响，为宿主易感性和耐药性提供了见解。综合计算策略为理解hbv -宿主相互作用提供了一个强大的框架，并可能有助于确定新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.