Recognition Mechanism Of Transcription Factor-DNA Specificity By Molecular Dynamics Simulation

The question of how DNA-binding proteins find its target navigating through billions of base pairs to locate the site is a hotspot and difficulty in transcription regulation and biomedical research.Studies have shown that the Sequence-specific binding mainly depends on two aspects: thermodynamics,which is determined by the relative affinity for a binding site on the DNA,and dynamic,depend on the kinetic formation of the transient complex in the search process.From the thermodynamic view,the binding of transcription factors to DNA has been widely studied.The main influencing factors include electrostatic attraction,hydrogen bonding,hydrophobic interaction and DNA shape dependent sequence.From the dynamics view,there are few related studies,and little is knowledge about the dynamic regulation mechanism of transcription factors binding to DNA.In this paper,the specific binding mechanism between transcription factors and DNA is taken as a scientific issue.The specific recognition mechanism of transcription factors and DNA was studied from thermodynamics and dynamics respectively.The research contents mainly include three aspects: firstly,the effect of single nucleotide polymorphism on the interaction between transcription factors and DNA was studied by molecular dynamics simulation.The second is to construct a base-pair stacking free energy matrix to study the important role of base-pair stacking in TF-DNA interaction and to predict the specific binding sites of transcription factors.Thirdly,a new one-dimensional sliding model of transcription factors was constructed,and the dynamic recognition mechanism of transcription factors and DNA was studied.We explored the effect of SNP on the specific binding of MEIS1 in an all-atom system.Our free energy calculations were in agreement with the experimental.Our simulations demonstrated that the mechanism by which SNP affects the transcription factor binding DNA is allosteric effect.The mutant site affected the DNA backbone by its own hydrogen bond interaction and then transcription factor binding the specific sequence becomes weaken because of changes of DNA groove.This long range interaction revealed that one mutation can transfer the effect by hydrogen bond interaction network.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 revealed that base-pair stacking can be used to predict TF binding specificity.The PMF results in the one-dimensional sliding model of transcription factors show that MEIS1 slides along the groove rather than along the linear.The recognition of the target sequence was speed up by one-dimensional diffusion of the protein along the DNA chain,during which the protein was loosely bound to nonspecific DNA.Markov state analysis shows that our results were consistent with the theory,and prove the DNA structure was play an important role in the sliding process.Based on the results of our MD,we infered the specific and non-specific 1D sliding length of MEIS1 along the DNA.MEIS1‘s asymmetrical domain dynamics and DNA structure in the DNA-scanning process can play an important role in resolving the speed-stability paradox.This work provides structural,dynamic,and kinetic information on how MEIS1 efficiently scans DNA to find its target sites rapidly.As such,this paper combined knowledge from bioinformatics and structural biology 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.The proposed mechanism has several important biological implications for search in the presence of other proteins,and provides a new framework for interpretation of experimental and structural data on protein-DNA interactions.