Data_Sheet_1_Trinucleotide Base Pair Stacking Free Energy for Understanding TF-DNA Recognition and the Functions of SNPs.xlsx

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（Single nucleotide polymorphisms, SNPs）可影响碱基堆积，而碱基堆积是维持DNA稳定性的首要因素。然而，单核苷酸多态性如何诱发表型变异的机制仍未阐明。本研究通过3聚体碱基堆积自由能矩阵（3-mer base pair stacking free energy matrix）将单核苷酸多态性与碱基堆积关联起来，且碱基堆积自由能差值较大的单核苷酸多态性会引发表型变异。随后本研究采用了分子动力学（molecular dynamics, MD）模拟方法，研究结果表明，碱基堆积在转录因子（transcription factor, TF）与DNA的相互作用中发挥着重要作用。DNA结构的变化主要源自转录因子与DNA的相互作用；随着碱基堆积自由能的升高，DNA结构会趋近于其游离状态，尽管该单核苷酸多态性会提升其结合亲和力。此外，基于碱基堆积特征构建的定量模型显示，碱基堆积可用于预测转录因子的结合特异性。综上，本研究结合了生物信息学与结构生物学的相关知识，为阐明单核苷酸多态性与表型变异之间的关联提供了新的认知。该3聚体碱基堆积自由能矩阵可用于单核苷酸多态性的高通量筛选以及转录因子-DNA结合亲和力的预测。