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.
Keywords: base stacking; binding specificity; free energy; molecular dynamics simulation; single nucleotide polymorphisms; transcription factor.