Insights into the DNA binding induced thermal stabilization of transcription factor FOXP3

The transcription factor FOXP3 is required for the development and function of regulatory T cells. Here, we studied the dynamics of FOXP3 in the presence and absence of DNA target sequence. Multiple molecular dynamics (MD) simulations were employed to investigate the role of DNA in enhancing the stability of FOXP3 via protein-DNA interactions, and to study the structural transition in protein at three different temperatures (300, 350, and 400 K). Results indicate that FOXP3 is stabilized by DNA even though the temperature rises up to 400 K. FOXP3 is found to undergo significant conformational change at a higher temperature, however, DNA provides greater rigidity and lower overall conformational flexibility, resulting in the global stabilization of FOXP3. The conformational restriction of FOXP3-DNA complex is probed with essential dynamics (ED). Free-energy landscape analysis at high temperature shows the presence of metastable intermediates, suggesting the reason behind the observed thermal stability. Secondary structural snapshots clearly indicate the presence of non-native interactions between DNA and protein. This study increases our understanding of the dynamic behaviors and the interaction mechanism of FOXP proteins and DNA at the atomic level and offers a model for studying the structural biology of transcriptional regulation.