Studies Of Solvation Free Energy, Binding Free Energy And Molecular Recognition In Terms Of ABEEMσπ/MM

The interactions between proteins and other molecules are crucial to many biological systems and processes. A reasonable representation of a protein’s environment is also important for characterizing these biological systems and processes. It has been well recognized that solvent effects have profound influences on the conformational stability and folding of proteins and on molecular recognition phenomena. Accurate, rapid and quantitative determination of solvation energies is an important problem in theoretical biophysics. To account accurately for the solvation energies arising in various and complex environments, both molecular (or explicit) and continuum (or implicit) models of solvent have been developed. Because the calculation of solute in molecular solvent models requires much more CPU time than that in gas phase, many researchers have a significant interest in developing more rapid continuum solvation models.One important thermodynamic quality is free energy, a measure of the stability of a system. In particular, free energy of binding is probably fundamental to all studies of biomolecular binding processes. It is central to well treat the electrostatic interaction for the calculation of the free energies, especially for the treatment of charge. This work was just based on the developed ABEEMσπ/MM (atom-bond electronegativity equalization method fused into molecular mechanics) fluctuating charge force field of Yang et al, which explicitly defines the charge regions of atoms, single bonds, double bonds, and lone-pairs, especially for double bonds with one σ and four π bond sites and the partial atomic charges can flow through chemical bonds from one atomic center to another depending on the different surrounding. Therefore, this method was further applied on the solvation free energy, binding free energy and molecular recognition. The main contents of this paper as following:(1) Calculations of solvation free energies based on ABEEMσπ/GBSA methodThe generalized Born/surface area (GB/SA) continuum model is a rapid and efficient method for the calculation of solvation energy. As a further development for GB model, this paper reports an effective way to improve the accuracy of the GB model in use of a fluctuating charge (FQ) model-the ABEEMσπ model. Because the partial atomic charges provided by the ABEEMσπ model can flow through chemical bonds from one atomic center to another based on the local electrostatic environment surrounding each atom, accurate and rapid calculations have been performed for series of compounds involving 105 small neutral molecules, twenty kinds of peptides and several protein fragments. It is shown that the combined ABEEMσπ/GB method has reproduced experimental results for small neutral molecules with a correlation of 0.97, a slope of 0.95, and a bias of 0.34 kcal/mol. Good agreements are also obtained from the comparison with ab initio and Poisson-Boltzmann (PB) calculations for dipeptides and protein fragments. This paper has proved the reliability of the combination of the GB model with the fluctuating charge protocol for computing electrostatic solvation energies.(2) Calculations of the binding free energies of receptor-ligand in terms of ABEEMσπ/MM-GBSAThe ABEEMσπ/MM combined with the Generalized Born Solvent Accessible surface area (GB/SA) method is proposed for calculating the binding free energies of receptor-ligand complexes. As a polarizable potential model, one very attractive feature of the ABEEMσπ/MM is to treat the charges on atomic, bond and lone pair’s sites that properly respond to the environment and conformational change. The methodology of estimating change in the binding free energy is divided into molecular mechanic energy, solvation energy and entropic contributions. Two systems have been calculated:(1) one system is systhezied receptor and ligand. The average unsigned error between the calculated and experimental data is less than 0.5 kcal/mol; (2) the other system is trypsin and five ligands. The average unsigned error between the calculated and experimental data is 0.85kcal/mol. The results demonstrate the transferability of the applied protocol to other protein systems. This approach also provides a way to shed light on the mechanistic basis for the protein-protein interactions at molecular level.(3) Studies of molecular recognition for receptor-ligandHow the receptor and ligand recognize each other is an argument subject in the process of explaining the mechanism of molecular recognition. As a starting point, a synthesized receptor and its ligand were chosen to simulate the process of recognition with the ABEEMσπ/MM method. It is found that a switch that was made up of a salt bridge in the ligand activated the recognition of receptor and ligand. In addition, the water molecules were important to the recognition which can act as a bridge connecting the active sites of the binding system. From the analysis of binding process, formation and activation of switch and water-mediated movement were corporately considered as the important factors for molecular recognition.(4) The construction of ABEEM ammonia-8P modelAmmonia is one of the most important solvent molecules. Structures, binding energies, and vibrational frequencies of (NH3)n (n= 2-5) isomers and dynamical properties of liquid ammonia have been explored using a transferable intermolecular potential eight points model including fluctuating charges and flexible body based on a combination of the atom-bond electronegativity equalization and molecular mechanics (ABEEM ammonia-8P) in this paper. The important feature of this model is to divide the charge sites of one ammonia molecule into eight points region containing four atoms, three σ bonds and a lone pair, and allows the charges in one molecule to fluctuate responding to the ambient environment.All in all, the establishment and application of the interaction function for biomacromolecule have infused into new vitality for the calculation of solvation free energy, binding free energy and molecular recognition. ABEEM polarizable force filed will play an important role in the fields of biological macromolecule in solutions, activity investigations of drug design and so on.