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

Abstract

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.

Structural and functional analysis of the human cone‐rod homeobox transcription factor

“…35 In addition, changing the base pair sequence alters the local base stacking energies, which affect the structure and dynamics of the DNA molecule. [46][47][48] Thus, within the broader context of the DNA molecule in the assay, the second site may not be the preferred binding site for CRX-DBD or the base substitution does not disrupt the contacts between the CRX-DBD and DNA under the assay conditions. Thus, CRX binding motifs may be a marker of potential CRX binding locations but there are additional effects that dictate CRX specificity.…”

“…Previously, we had shown the effects of DNA methylation on the structure of DNA and the CRX binding motif 35 . In addition, changing the base pair sequence alters the local base stacking energies, which affect the structure and dynamics of the DNA molecule 46–48 . Thus, within the broader context of the DNA molecule in the assay, the second site may not be the preferred binding site for CRX‐DBD or the base substitution does not disrupt the contacts between the CRX‐DBD and DNA under the assay conditions.…”

Structural and functional analysis of the human Cone-rod homeobox transcription factor

“…Previously, we had shown the effects of DNA methylation on the structure of DNA and the CRX binding motif 26 . In addition, changing the base pair sequence alters the local base stacking energies, which affect the structure and dynamics of the DNA molecule [32][33][34] . Thus, within the broader context of the DNA molecule in the assay, the second site may not be the preferred binding site for CRX-DBD or the base substitution does not disrupt the contacts between the CRX-DBD and DNA under the assay conditions.…”

Detection of Single Nucleotide Polymorphisms by Fluorescence Embedded Dye SYBR Green I Based on Graphene Oxide

“…Single nucleotide polymorphisms (SNPs) are extremely important genetic variations in human genes ( Martin et al, 2020 ). SNPs research is closely related to the development of pharmacogenomics and disease diagnosis, and is an important step toward the application of human genome projects ( Li et al, 2019 ). At present, there are many methods for detecting SNPs ( Uppu et al, 2016 ; Zhao et al, 2018 ; Prezza et al, 2019 ), including gene sequencing technology ( Kim et al, 2016 ), capillary electrophoresis technology ( Zhao et al, 2019 ), reversed-phase high performance liquid chromatography (HPLC) detection ( Jones et al, 1999 ; Tonosaki et al, 2013 ), gene chip technology ( Tu et al, 2018 ), etc.…”