Effect Of Nanoparticles And Environmental Water On The Protein Conformation: Molecular Dynamics Simulation Studies

Proteins are the fundamental unit of life. It is not only the essential component in the structure of living forms, but also performs many vital functions in life. The system of proteins is an important object of molecular biology, bioinformatics and drug design. Understanding of the folding and conformation of protein is a key topic in protein research, which is of great importance to both the basic scientific research and the life and health of human. With the fast development of computer techniques, the numerical simulation, which can mimic this kind of interaction, has become a powerful tool in the studies of protein structure and conformational variation, and play an irreplaceable role in this field.In this thesis, we report our studies on the protein structure and conformational variation by using the molecular dynamics simulation. Various molecular models, in-cluding the classical Go-like model, the desolvation Go-like model, and the all-atom model, are used for different problems. In detail, there are seven chapters in our thesis:In the first chapter, we give an introduction. Some physical problems related to the protein structures field are also briefly reviewed, as well as the introduction of some frequently-used methods in both experiment and computer simulation.In the second chapter, we report our studies on the effect of the ordered water on protein folding. Here, the ordered water is the water which confined on the surface of some substrates, including the surfaces of cellular components in tissues and cells, and form icelike ordered structures. We use an off-lattice Go-like model together with an introduction of a phenomenal equation for the main characteristic of the ordered structure of water. The molecular dynamics shows that the ordered water environment significantly improves the native state stability and greatly speeds up the folding rate of the proteins.In the third chapter, the effect of solvation-related interaction on the low-temperature dynamics of proteins is studied using a variant of Go model by taking into account the desolvation barriers in the interactions of native contacts. It is found that about the folding transition temperature, the protein folds in a cooperative behav-ior, and the water molecules are expelled from the hydrophobic core at the final stage in the folding process. At low temperature, however, the protein is generally trapped in many meta-stable conformations with some water molecules frozen inside the protein. The number of frozen water molecules and that of frozen states of proteins are further analyzed with the methods based on principal component analysis (PCA) and the clus-tering of conformations. It is found that both the numbers of frozen water molecules and the frozen states of the protein increase quickly below a certain temperature. Es-pecially, the number of frozen states of the protein increases exponentially following the decrease of the temperature, which resembles the basic features of glassy dynam-ics. Interestingly, it is observed that the freezing of water molecules and that of protein conformations happen at almost the same temperature. This suggests that the solvation-related interaction performs an important role for the low-temperature dynamics of the model protein.In the forth chapter, we perform the simulation on the folding of a helix-turn-helix from a partial unfolded conformation, in which one helix is unfolded and the other is remained, to the state which conformation is very similar to the native conformation in explicit water. It is found that in the folding pathway, the protein form the secondary and tertiary structure step by step. Between the folding of the secondary and tertiary structure, there are misfolded structures formed and then unfolded. In other pathways, the protein is trapped in the misfolded structures, including the two-helix and three-helix whose energies are not optimized for this peptide. Based on the analysis of the interactions between protein and water, we find that the energy interaction between the water molecules are also very important for the folding of protein.In the fifth chapter, we study the interaction between the nanoparticle and protein by using an all-atom model. As we all known, nanoscale particles have become promising materials in many fields, including cancer therapeutics, diagnosis, imaging, drug de-livery, catalysis, and biosensors. In order to stimulate and facilitate these applications, there is an urgent need for the understanding of the interaction between nanomaterials and the biological systems, nanotoxicity and other risk involved with these nanomate-rials to human health. In this study, we use large scale molecular dynamics simulations to show that a pristine carbon nanotube, one form of hydrophobic nanoparticle, can un-expectedly plug into the hydrophobic core of proteins, such as WW domains, to form stable complexes. This plugging of nanotubes disrupts and blocks the active sites of WW domains from binding to the corresponding ligands, thus leading to the loss of the original function of the proteins. The key to this observation is the hydrophobic interac-tion between the nanoparticle and the hydrophobic residues, particularly tryptophans, in the core of the domain. We believe that these findings might provide a novel route to the nanotoxicity on the molecular level for the hydrophobic nanoparticles.In the sixth chapter, we study the binding competition between the ligand and the nanoparticle on the target protein. Similar to the study in the previous chapter, this chapter is also relative to the nanotoxicity. It had been reported that the primary in-teraction between the target protein and its ligand is the hydrophobic interaction. That is, there is a hydrophobic area, which can bind the hydrophobic ligands as well as the hydrophobic nanoparticles, on the surface of the target protein. Our simulation study shows that the pristine carbon nanotube, which is more hydrophobic than most of lig-ands, can firmly bind on the hydrophobic surface of the target protein and make the binding site of ligand occupied. This may lead the loss of the function of the target protein.In the last chapter, we give a summary about our studies. Some issues on the mod-eling of protein structures are also discussed. The competition between the coarse-grained model and all-atom model are addressed based on our experiences. We believe these are helpful to the further studies in this field.