Elucidating Electronic Structure Variations in Nucleic Acid-Protein Complexes Involved in Transcription Regulation Using a Tight-Binding Approach

Abstract Transcription factor (TF) are proteins that regulates the transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. Nucleic acid-protein interactions are crucial in regulating transcription in biological systems. This work presents a quick and convenient method for constructing tight-binding models and offers physical insights into the electronic structure properties of transcription factor complexes and DNA motifs. The tight binding Hamiltonian parameters are generated using the random forest regression algorithm, which reproduces the given ab-initio level calculations with reasonable accuracy. We present a library of residue-level parameters derived from extensive electronic structure calculations over various possible combinations of nucleobases and amino acid side chains from high-quality DNA-protein complex structures. As an example, our approach can reasonably generate the subtle electronic structure details for the orthologous transcription factors human AP-1 and Epstein-Barr virus Zta within a few seconds on a laptop. This method potentially enhances our understanding of the electronic structure variations of gene-protein interaction complexes, even those involving dozens of proteins and genes. We hope this study offers a powerful tool for analyzing transcription regulation mechanisms at an electronic structural level. Topic of Content Transcription factors that bind to DNA modulate gene expression, with the stability and reactivity of their interactions elucidated by eigenvalues derived from the tight-binding model. Visualization of these interactions reveals the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO), the gap between which determines the reactivity and stability of the molecular complex. This approach advances our understanding of gene regulation by revealing the dynamics of charge transfer and electronic states within transcription factor-DNA complexes.