| Proteins are fundamental to all life activities and play essential roles in eachbiological process in living cells. Various biological functions of protein are related tothe3D structure. In other word, a protein needs to fold into a specific structure beforeperforming the biological function. Proteins mainly consist of20common aminoacids. It has attracted lots of research interest on how a sequence of amino aciddetermines a specific3D structure and then performs a biological function. Thefunction of protein cannot be performed without interactions with other molecules.These molecules that interact with a protein are called ligands, including proteins,peptides, DNA, RNA, small molecules and so on. The process of protein function canbe reduced to three steps: bind, transform and release. Studies on the structure andrecognition mechanism of protein-ligand complex will help us to further understandthe fundamental process of life.The purpose of researches on the structure and function of protein is not only toexplore the basic process of life, but also to promote the rapid development ofnumerous applications, including protein evolution engineering, bio-pharmaceutical,monitoring and control of environmental pollution and so on. Some characteristics ofprotein, for example the catalytic efficiency and specificity of enzyme, make itpopular in industrial applications. However, in actual industrial production conditions(extreme environment like high temperature, high pressure, and extreme pH), thestructure and function of natural proteins tend to be destroyed. Studies on the stabilityof protein will be helpful to the design of new proteins for industrial applications. Inthe field of medicine, more and more proteins have been connected to variousdiseases and have been considered as drug targets. The drug design based on proteintargets has become an important part of drug research. Small molecules, proteins andpeptides can be used as drugs, working through interactions with target proteins.Studies on the interaction and recognition mechanism of protein-ligand complex arehelpful to the drug design. Numerous proteins are not only the targets of drugs, butalso the targets attacked by pollutants. Lots of studies have connected the exposure ofpollutants with various diseases, in which pollutants enter into human body and thenbind to proteins disrupting their normal functions. Studies on the interactions betweenproteins and pollutants will help us to further understand the pathogenic mechanismon diseases caused by pollutants. Besides, tt can also provides useful information forthe design of biosensor for the environmental monitoring and catalytic enzyme for thedegradation of pollutants.The work in this paper mainly contains following contents:(1) Thermal stability and unfolding pathway of a hyperthermophilic protein and its mutant;(2) Steeredmolecular dynamics of an anticancer peptide interacting with the tumor suppressorp53;(3) Interactions and inhibitory mechanism of persistent organic pollutants (POPs)agonist protein receptors;(4) Reverse virtual screening on POPs. The detailed studyresults are described as below:(1) Thermal stability and unfolding pathway of Sso7d and its mutantSso7d is a small DNA binding protein from the hyperthermophilic archaeonSulfolobus solfataricus with a denaturation temperature of98°C at neutral pH. Analanine substitution of phenylalanine31will significantly reduce the protein thermo-and piezostabilities. Here, the thermo-stability and unfolding behaviors of Sso7d andits mutant are studied by molecular dynamics simulation at temperatures of300,371and500K. The results show that hydrogen bonds, salt bridges, hydrophobic core,aromatic cluster and secondary structural elements play important roles in preservingthe stability of Sso7d. Besides, the results from high temperature simulation show thatthe wide type protein and the mutant have different unfolding pathways.(2) Steered molecular dynamics of an anticancer peptide p28interacting with thetumor suppressor p53Recent studies have reported that a28-amino-acid peptide fragment (p28) fromthe blue copper azurin, can enters into cancer cells, forms a complex with thetranscription factor p53, and then inhibits cancer cell proliferation. The Atomic ForceSpectroscopy (AFS) study on p28and p53reveals that p28binds to p53DNA-bindingdomain (DBD). Here we have applied Steered Molecular Dynamics (SMD) to thecomplex formed by p53DBD and p28. The time evolution of the system during thepulling can be followed at atomic resolution, enabling to disclose subtle moleculardetails underlying the unbinding process. Furthermore, using suitably theoreticalmodels allows us to obtain information on the energy landscape and on thethermodynamic properties of the complex. These results shed light on the molecularmechanisms regulating the complex formation whose knowledge, in turn, could helpfor tailoring the peptide molecular structure in order to achieve an enhancedanticancer activity.(3) Studies of interactions between POPs and protein receptorsPOPs is a kind of pollutants with characteristics like persistent in theenvironment, bioaccumulate, high toxicity, and the capable of long-range transport.POPs exposure can cause various diseases in human and wide life. It has become anew environmental problem. Studies have revealed that POPs can bind to someproteins in body and disable their functions causing related diseases. Our studies aremainly focused on three common POPs: TCDD,4,4’-DDE and CB-153. Studies on toxic effects induced by TCDD show that it binds to aryl hydrocarbonreceptor (AhR) disrupting related genes expression. Meanwhile, TCDD can inhibit theactivity of casein kinase II (CK2). We employed computational modeling methods,such as molecular similarity, molecular docking, molecular dynamics, and bindingfree energy calculation, to study the inhibitory mechanism of TCDD agonist CK2, andpredicted their binding modes.4,4’-DDE is the major metabolite of the widely used organochlorine insecticidedichlorodiphenyltrichloroethane (DDT) and CB-153is one of the most commoncongeners of polychlorinated biphenyls (PCBs). Studies show that they belong toenvironmental endocrine disruptors (EEDs) and are responsible for some reproductivediseases. Recent studies revealed that4,4’-DDE is an antagonist of androgen receptor(AR), but the mechanism of the inhibition remains elusive. Although some studyshow that CB-153is also an antagonist of AR, it is still under debate. We employedcomputational modeling methods like molecular docking, molecular dynamics, andbinding free energy calculation, to predict binding modes of these two POPs agonistAR. The possible inhibition mechanism has also been analyzed.(4) Reverse virtual screening on POPsThere exist various kinds of proteins in an organism. Once inside a body, POPs mightbe able to interact with different proteins, causing related diseases. Determining theprotein receptors for POPs will be useful for the further understanding of toxicmechanism. Besides, it can provide useful information for related applications such asthe design of recognition elements in biosensor. Here, reverse virtual screeningapproach has been employed on POPs to search potential protein targets. In detail,4,4’-DDE and CB-153were docked to all proteins in a protein structure database.Then these proteins are ranked according to values of binding free energy to findpossible receptors. According to experimental information, these potential targets arelinked to related diseases. |
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