Li Gen, Quan Yuan, Wang Xiaocong, Liu Rong, Bie Lihua, Gao Jun, Zhang Hong-Yu
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China.
Front Chem. 2019 Jan 18;6:666. doi: 10.3389/fchem.2018.00666. eCollection 2018.
Single nucleotide polymorphisms (SNPs) affect base pair stacking, which is the primary factor for maintaining the stability of DNA. However, the mechanism of how SNPs lead to phenotype variations is still unclear. In this work, we connected SNPs and base pair stacking by a 3-mer base pair stacking free energy matrix. The SNPs with large base pair stacking free energy differences led to phenotype variations. A molecular dynamics (MD) simulation was then applied. Our results showed that base pair stacking played an important role in the transcription factor (TF)-DNA interaction. Changes in DNA structure mainly originate from TF-DNA interactions, and with the increased base pair stacking free energy, the structure of DNA approaches its free type, although its binding affinity was increased by the SNP. In addition, quantitative models using base pair stacking features revealed that base pair stacking can be used to predict TF binding specificity. As such, our work combined knowledge from bioinformatics and structural biology and provided a new understanding of the relationship between SNPs and phenotype variations. The 3-mer base pair stacking free energy matrix is useful in high-throughput screening of SNPs and predicting TF-DNA binding affinity.
单核苷酸多态性（SNP）会影响碱基对堆积，而碱基对堆积是维持DNA稳定性的主要因素。然而，SNP导致表型变异的机制仍不清楚。在这项工作中，我们通过一个三联体碱基对堆积自由能矩阵将SNP与碱基对堆积联系起来。具有大的碱基对堆积自由能差异的SNP会导致表型变异。随后进行了分子动力学（MD）模拟。我们的结果表明，碱基对堆积在转录因子（TF）-DNA相互作用中起重要作用。DNA结构的变化主要源于TF-DNA相互作用，并且随着碱基对堆积自由能的增加，DNA结构接近其自由状态，尽管SNP增加了其结合亲和力。此外，使用碱基对堆积特征的定量模型表明，碱基对堆积可用于预测TF结合特异性。因此，我们的工作结合了生物信息学和结构生物学的知识，为SNP与表型变异之间的关系提供了新的理解。三联体碱基对堆积自由能矩阵在SNP的高通量筛选和预测TF-DNA结合亲和力方面很有用。
