Study On The Ligand Escape Pathways For The PPARγ–TBBPA Complex

With the implementation and promoting of the human genome sequencing project, the research of life science has came to the post-genomic era, which mainly focuses on functional genomics and proteomics. Proteins are the material basis of life, and also the main bearer of all life activities. They play essential roles in every biological process of living life. Researches on the relationship between structure and function of protein will clarify the biological process of life phenomena directly. One of the important ways through which proteins perform their biological functions is to interact with other molecules which are called ligands, including DNA, RNA, proteins, peptides, small molecules and so on. Studies on the interaction between the protein and ligand will not only contribute to better understanding the regulatory mechanism of organism, but also provide important theoretical basis to the investigation of molecular mechanisms that generate major diseases, the rational drug design and the environmental pollution monitoring.Pollutants that produced by human life closely relate to the occurrence of many diseases. Some contaminant molecules would interact with proteins of the body after they are ingested by human. Then the normal physical functions of corresponding proteins will be disrupted. And they eventually lead to the occurrence of the disease. However, through which pathway did the small molecule compounds enter the receptor proteins and reach the binding sites, and how did they dissociate out of the proteins are still difficult questions in understanding the molecular pathogenesis of pollutants. In this paper, the dissociation pathway of the additive of plastic products tetrabromobisphenol A(TBBPA) from its receptor protein were studied through computer simulation methods. The contents in this paper mainly contain two parts as follows:(1) Study on the dissociation pathway of TBBPA from the receptor protein with random acceleration molecular dynamicsTetrabromobisphenol A is a halogenated derivative of bisphenol A. It is an important kind of plastics additive, and also a commonly used flame retardant. TBBPA is a potential endocrine disrupting chemical, which would lead to human diseases after a long time exposure. The study shows that TBBPA can function as obesogens by acting as agonists to disrupt normal physiological functions regulated by peroxisome proliferator-activated receptor γ(PPARγ). Here, the dissociation pathway of TBBPA from the receptor protein is studied by random acceleration molecular dynamics. By multiple simulations, we found three possible dissociation pathways. Additionally, we found that the flexibility of protein itself plays an important role in the release of the ligand. These results provide the information about stretching directions for the subsequent steered molecular dynamics simulations(2) Steered molecular dynamics simulations of TBBPA and receptor proteinOn the basis of random acceleration molecular dynamic simulations, we investigated the detailed information on the dissociation process of TBBPA from PPARγ at the atomic resolution through the steered molecular dynamics simulations(SMD). For each potential dissociation pathway, we carried out 50 trajectories of SMD simulations. Subsequently, the potential of mean force through each pathway were calculated using the Jarzynski’s equations. The results show that TBBPA is very likely to be dissociated in a conservative pathway from the receptor. And the H bonds play a vital role in the process of ligand dissociation. These results not only reveal the molecular mechanism of the formation process of PPARγ- TBBPA complex, but also are helpful for rational drug designing with PPARγ as a target protein.