| With the rapid development of computer, Molecular dynamics (MD) simulation has increasingly applied in all kinds of simulation system since1970. The core of the MD simulation is the force field, which is incomplete or not has a significant impact for the correct degree of the simulation. The common force field contains the potential energy function and its corresponding force field parameters, which has been successfully used in many molecular domains because of its simplicity. We can calculate the interactions between molecular with force filed. But the force field also has its disadvantages:because of the function of the biological molecules associated with the dynamic changes of its three-dimensional structure in the biological environment. However, the polarization effect of water is very significant, unfortunately, which is not included in this force field. In particular, the force field parameters widely used for water molecules are fixed from the structure, dynamical and thermodynamic properties of water molecules, such as radial distribution function, diffusion coefficient and evaporation enthalpy etc. which does not considering cooperate with protein directly. In addition, the force field does not contain all the small molecular information, so we need to generate template according to our needs.In this article, first, we study the electrostatic polarization effect with the comparison between polarized protein-specific charge (PPC) and AMBER charge; Second we explore the influence of organic molecules2,2,2-Trifluoroethanol (TFE) on protein structure. Namely, this article contains mainly two parts:one is protein-water hydrogen bonds are stabilized by electrostatic polarization, the other is equilibrium and folding simulation of NS4B in pure water and water/2,2,2-trif luoroethanol mixed solvent. The main contents and results obtained in the thesis are as follows:I. Protein-water hydrogen bonds are stabilized by electrostatic polarization.In order to avoid the dependence of water model, both TIP3P and SPC/E water models are utilized. We chose the TIP3P because of it is used with the AMBER force filed frequently, while SPC/E is good agreement with experiment on dynamical properties.1. PPC fitThe protein achieved equilibrium in water through equilibrium simulation. And then PPC was calculated on the equilibrium. The protein decomposed into residues with the conjugate caps (MFCC) scheme, and then added proper caps to each fragment n order to saturate the covalent bonds and also to mimic the chemical environment. First the initial electron density distribution of each segment was calculated with quantum mechanical calculation in the gas phase, and then the charge of every atom was fitted through the RESP method. The induced charges on protein-solvation interface, which is represent the solvation effect, were obtained by solving PB equation. The induced charge and other residues are taken as background charges fixed until solvation energy and protein charges converged. Therefore, PPC gives a more accurate description of charge distribution than traditional force fields.2. MD simulation and resultsAnd then, we studied the dynamical properties of the hydration water around the protein in this thesis under traditional AMBER charge and PPC, which taken polarization effect into it. Results showed that:(1) For both water models, the main chain atoms are relatively stabilize than the side chain atoms under AMBER charges and PPC.(2) With the polarization effect taken into consideration as in the PPC, protein-water hydrogen bonds are strengthened and broken hydrogen bonds have larger possibility to reform.(3)From the analysis of the dynamical properties of the water molecules bonded to the protein, we found that both the translational and rotational motions of the water molecules are hindered.II. Equilibrium and folding simulation of NS4B in pure water and water/2,2,2-trifluoroethanol mixed solvent.1. Building50%v/v TFE/water mixed solvent modelThe peptide NS4B is a α-helix, which was solved in50%v/v TFE/water mixed solvent. Therefor we need to build the mixed solvent model first. The initial structure of TFE was built by GaussView, and then optimized at HF/6-31G**level using Gaussian09. Atomic charges of TFE were fitted according to the dual-step restrained potential (RESP) method. The50%TFE/water mixed solution was generated by putting1:4TFE and water molecules in a periodic box, and then carried out equilibrium simulation until the system achieved equilibrium.2. Equilibrium simulation and folding simulationIn equilibrium simulation, both explicit solvation model (water and TFE/water mixed solvent)and GB model (water, TFE/water mixture and pure TFE) were used. In GB model, the continuum solvent area was setted a dielectric constant of78.5,53.0and27.1for water, TFE/water mixture and pure TFE respectively.Based on the result shown in equilibrium simulation, the result from the simulation of GB water/TFE model was against that from the explicit water/TFE cosolvent. Therefor the folding simulation of the protein was carried out in explicit water/TFE cosolvent. Two independent folding simulations were carried out from sequence structure.3. Analysis and conclusionIn this paper, the peptide is observed to be partly unfolded in water but readily stabilized in an ordered helical conformation in water/TFE mixture, in agreement with the experimental observation. Furthermore, the simulations show that the accumulation of TFE molecules in immediate environment of the peptide, which prevents the formation of alternative hydrogen bonds between water and the peptide. Besides, it provides a low dielectric environment that stabilizes the main chain hydrogen bonds in the peptide.The peptide was very flexible in implicit water, which is consistent with the simulation in explicit water. However, discrepancy between simulations in GB and in explicit water/TFE mixture can be noticed. It might be argued that the first solvation shell of peptide in mixed water/TFE is mainly occupied by TFE molecules. Therefore the dielectric constant is different from the macroscopic measurement. To examine this conjecture, a simulation in implicit solvent with the dielectric constant set to that of pure TFE was also performed. But the result did not show any improved stability of this peptide over that in ε=53.0. This result shows that implicit solvent model like GB is not a good model for TFE or water/TFE mixed solvent.Two folding simulations have been performed in explicit water/TFE solvent. These two trajectories show only trivial differences. The folding takes place mainly from central residues, and elongates towards the terminals. The helical segments merge together in the final stage. Furthermore, the folding is accompanied by the aggregation of TFE molecules on the peptide surface. This coating effect promotes the formation of local interactions and, as a consequence, ordered secondary structure. This observation is consistent with the experimental understanding that TFE is an effective trigger of secondary structure, especially the helical conformation. |
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