An Attempt of Seeking Favorable Binding Free Energy Prediction Schemes Considering the Entropic Effect on Fis-DNA Binding.

Protein-DNA binding mechanisms in a complex manner are essential for understanding many biological processes. Over the past decades, numerous experiments and calculations have analyzed the specificity of protein-DNA binding. However, the accuracy of binding free energy prediction for multi-base DNA systems still needs to be improved. Fis is a DNA-binding protein that regulates various transcription and recombination reactions. In the present work, we tested several methods of predict binding free energy based on this system to find a favorable prediction scheme and explore the binding mechanism of Fis protein and DNA. Two solvent models (explicit and implicit solvent models) were chosen for the dynamics process, and the predicted binding free energy was more accurate under the explicit solvent model. When different Poisson-Boltzmann/Generalized Born (PB/GB) models were tested for DNA force fields (BSC1 and OL15), it was found that the binding free energy predicted by the selected OL15 force field performed better and the correlation between predicted and experimental values was improved with the increasing interior dielectric constant (Dk). Finally, using Dk = 8, the GB OBC1 model combined with interaction entropy (IE), which was calculated for entropic contribution (GB OBC1 _IE_8), was screened out for the binding free energy prediction and analysis of the Fis-DNA system, and the validity of the method was further verified by testing the Cren7-DNA system. By performing conformational analysis of the minor groove, it was found that mutation of the DNA central sequence A/T to C/G and deletion of the guanine 2-amino group would change the minor groove width and thus affect the formation of the major groove, altering the interaction and atomic contact between the protein and the major groove, thus changing the binding affinity of Fis and DNA. Hopefully, the series of tests in this work can shed some light on the related studies of protein and DNA systems.