The Computational Simulation Study Of Two DNA-binding Proteins To Recognize Target Sites

How DNA-binding proteins anchor DNA target sites in vast genomic sequences is an important scientific issue.Existing models show that DNAbinding proteins may anchor target sites through three-dimensional hopping,one-dimensional sliding,or multiple modes of facilitated diffusion,and inducing DNA deformation,and their conformational changes.Thymine DNA glycosylase(TDG)and the transcription factor Homeobox D9(HoxD9)may recognize their target sites through the above-mentioned mechanism.TDG participates in gene repair by recognizing then excising mismatched or damaged bases.HoxD9 participates in transcription by recognizing specific sequences of promoters.Abnormal function of them will lead to many diseases.At present,the above-mentioned mechanism that TDG and HoxD9 recognize their target sites still lack atomic-level analysis on a dynamic process.An in-deep understanding of the molecular recognition mechanism of TDG and HoxD9 to target sites will provide theoretical guidance for the design of high-efficient drugs in the future.In this paper,we will study the molecular recognition process of TDG and HoxD9 to target sites using computational molecular simulation methods.The main work of this article is as follows:1)We explored how TDG responds to different DNA bending conformations by constructing TDG-DNA complexes containing different DNA bending conformations and performing molecular dynamics(MD)simulation.The results showed that TDG is favor of the DNA conformations bents at 20°-30°,the key structural fragment(Lys232-Phe252)of TDG recognizes specific DNA bending structures.Moreover,Lys232,Lys240,and Lys246 are crucial for the molecular recognition of TDG to DNA.The results also revealed that the DNA roll angle is closely related to the DNA bend angle,and further dominates the TDG combination.This study reveals the recognizing features of TDG to different bending DNA at the atomic level.2)We obtained the path of HoxD9 sliding along with DNA by constructing multiple HoxD9-DNA complex structures and performing targeted molecular dynamics(TMD)simulation.Then,the obtained highdimensional data was submitted to dimensionality reduction.Based on the low-dimensional data,we obtained 100 central structures of microstates.Next,we performed a 20-ns MD simulation for each above central structure,and the microstates were collected again for the last 10-ns MD simulation and 100 central structures were obtained.The next step in this study is to conduct two rounds of MD simulation and build a markov states model(MSM)to reveal the mechanism of HoxD9 searching for its specific sequence from the molecular level.