Calculation Of The Binding Free Energy Of Enzyme/Inhibitor And The Dynamic Simulation Of β-hairpin Fragment In Aqueous Solution By Means Of ABEEMσπ/MM Method

In drug design, enzyme as a drug target has a long history and is still important to study. Many of the clinical application of drugs by specifically inhibit or activate (in fewness) the activity of the enzyme to play a role. The statistics show that about one-third of clinical drugs are enzyme inhibitors. Therefore, the exploration and research on the interaction between the enzyme and ligand is crucial of the development and design of new drugs. Simultaneously, with the development of computer science, it provides a good hardware platform for the investigation of the ligand-receptor interactions of high-precision theoretical calculations (such as the calculation of binding free energy). Therefore, the various force filed have developed and applied to the study the enzyme structures and the computer-aided drug design.Computer-aided drug design is the application of quantum chemistry, molecular dynamics, QSAR, and other basic data to study the role of efficacy model of drugs on the enzyme or receptors. The commonly used method in computer-aided drug design is molecular docking method. The purpose of docking is to find the best combination of location and how to evaluate the bonding strength between the donors and receptors. Therefore, molecular docking faces two important questions:how to find the best combination of location and how to evaluate the bonding strength between the molecules, and these two issues in the docking calculation is interrelated. How to find the best combination of positions referred to structural optimization. The second problem is related to the estimation of the binding free energy of the donors and receptors. The prediction of the binding free energy is the core issues of the computer-aided drug design. A variety of methods have been proposed for estimating the binding free energy. But there are some limitations and questions. So to propose a method to estimate the binding free energy accurately and quickly is the key issue of current drug design.In this dissertation, based on the atom-bond electronegativity equalization model and Generalized Born (GB) continuum model calculation of electrostatic salvation, we proposed a method to estimate the absolute free energy of binding. The parameters of this method are calibrated by using a training set of 24 HIV-1 protease-inhibitor complexes. The present approach is further tested on seven inhibitor and protease complexes, and provides small rms deviation between the calculated binding free energy and experimental binding free energy. Furthermore, we apply the method to calculate the binding free energies between the cyclooxygenase-2 (COX-2) and inhibitors as well as β-secretase (BACE) and inhibitors without reparametrization. The calculated results are discussed in detail. Moreover, we have extended the ABEEMσπ force filed to the molecular dynamics simulations of a β-hairpin Fragment in solution and the hydration of formic acid. The main contents of the dissertation include the following:(1) The application of the ABEEMσπ/MM method to calculate the binding free energy of HIV-1 protease and inhibitorsA method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. The linear interaction energy (LIE) method is combined with ABEEMσπ Force field (atom-bond electronegativity equalization method fused into molecular mechanics) and Generalized Born (GB) continuum model calculation of electrostatic solvation for the estimation of the absolute free energy of binding. The binding free energy formula is used for the fitting of a three-parameter model: and a two-parameter model:The parameters of this method are calibrated by using a training set of 24 HIV-1 protease-inhibitor complexes (PDB entry 1AAQ). A correlation coefficient of 0.93 and 0.91 were obtained with a root-mean-square (rms) deviation of 0.70,0.77 kcal/mol, respectively. The mean unsigned deviations values are 0.56,0.55 kcal/mol, respectively. The present approach is further tested on seven inhibitor and protease complexes, and provides small rms deviation between the calculated binding free energy and experimental binding free energy without reparametrization. Through comparing the radii of gyration and the hydrogen bond distances between ligand and protein of three training model molecules, gain the consistent comparison result of binding free energy. It proves that the present method for calculating the binding free energy with appropriate structural analysis can be applied to quickly assess new inhibitors of HIV-1 proteases.(2) The investigation of the interactions between the cyclooxygenase-2 (COX-2) and inhibitors as well as β-secretase (BACE) and inhibitorsWe extended the method to calculate the binding free energy of cyclooxygenase-2(COX-2)/inhibitors and β-secretase (BACE)/inhibitors. The method which is proposed to estimate the binding free energy in terms of ABEEMσπ/MM and continuum electrostactics fused into LIE method. In the same time, we also calculated the relative binding free energies for the series of inhibitors and COX-2. The calculated results were compared with the results from the experiment. On the one hand, the transferability of the parameters can be checked. On the other hand, we combined the discussion of the charge distributions and the calculation of relative binding free energies to estimate the bonding strength between the different inhibitors.(3) Molecular Dynamics Simulations of a β-hairpin Fragment by Means of ABEEMσπ/MM methodThere are some controversial opinions about the origin of folding β-hairpin stability in aqueous solution. In this study, the structural and dynamic behavior of a 16-residue β-hairpin from B1 domain of protein G has been investigated at 280 K,300 K,350 K and 450 K using molecular dynamics (MD) simulations by means of Atom-Bond Electronegativity Equalization Method Fused into Molecular Mechanics i.e., (ABEEMσπ/MM) and the explicit ABEEM-7P water solvent model. In addition, a 300 K simulation of one mutant having the aromatic residues substituted with alanines has been performed. The hydrophobic surface area, hydrophilic surface area and some structural properties have been used to measure the role of the hydrophobic interactions. It is found that the aromatic residues substituted with alanines have shown an evident destabilization of the structure and unfolding started after 1.5 ns. It is also found that the number of the main chain hydrogen bonds have different distributions through three different simulations. All above demonstrate that the hydrophobic interactions and the main chain hydrogen bonds play an important role in the stability of the folding structure of (3-hairpin in solution. Furthermore, through the structural analyses of the β-hairpin structures from four temperature simulations and the comparison with other MD simulations of β-hairpin peptides, the new ABEEMσπ force field can reproduce the structural data in good agreement with the experimental data.(4) Theoretical studies on the hydration of formic acid by ABEEMσπ fluctuating charge modelThe interaction between formic acid (FA) and water was systemically investigated by atom-bond electronegativity equalization method fused into molecular mechanics (ABEEMσπ/MM) and ab initio methods. The geometries of 20 Formic acid-water complexes (FA-(H2O)n(n=1-3)) were obtained using B3LYP/aug-cc-pVTZ level optimizations, and the energies were determined at the MP2/aug-cc-pVTZ level. The 20 Formic acid-water complexes have been employed to study the optimal structures, charge distributions, and interaction energies. The ABEEMσπ potential model gives reasonable properties of these clusters when comparing with the present ab initio data. For interaction energies, the root mean square deviation is 0.74 kcal/mol, and the linear coefficient reaches 0.993. Next, FA in aqueous solution was also studied. The hydrogen-bonding pattern due to the interactions with water has been analyzed in detail.(5) The corresponding programs are compiled by us. We own the independent intellectual property right.All in all, based on the atom-bond electronegativity equalization model and Generalized Bom (GB) continuum model calculation of electrostatic salvation, we proposed a method to estimate the absolute free energy of binding. The method is applied to calculate the binding free energies of HIV-1 protease and inhibitors successfully, and the calculated results are better than results with the other methods. In addition, we apply the method to calculate the binding free energies between the cyclooxygenase-2 (COX-2) and inhibitors as well as β-secretase (BACE) and inhibitors. From the calculated results we gain the conclusion that the parameters are not transferable between HIV-1 PR and other systems. Although there are some questions to account for this method, the present method can be applied to quickly assess new inhibitors of HIV-1 proteases, and to predict the binding strength between the different inhibitors of other enzymes without reparametrization. The present method to calculated the binding free energy is extended the applying of ABEEMσπ fluctuating charge model...