Theoretical Studies of Aqueous Solvation of Proteins

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9506796 Ichiye The development of theories of aqueous solvation of biological macromolecules is crucial to understanding their structure and function. This research will develop theories for macromolecular solvation and implement them into simulation algorithms and to study specific interactions of water and counterions with proteins. Simple continuum solvent models are insufficient to describe phenomena such as hydrogen bonding, local dielectric perturbations and phenomena involving separations of only a few water layers. To understand and model the molecular nature of solvation, the approach used here is the development of statistical mechanical integral equation theories. First, the previously proposed integral equation theory for solvation of globular molecules will be extended to proteins. To facilitate this, a new model of water for simulations will be developed, which is equivalent to TIP4P in structural properties but is three times faster than 3-site water models in Monte Carlo simulations. Without further development, this theory can then be used to predict the solvation of a given structure; e.g., a crystal or NMR structure of a protein. Second, this theory of aqueous solvation of macromolecules will be incorporated into dynamics simulation algorithms. Currently, addition of explicit solvent into a molecular dynamics simulation is the only simulation method to include the molecular nature of water, but it is very costly in computer resources. Several different methods of incorporating this theory are discussed. The final goal is incorporation of ionic strength effects into simulation methods. %%% The development of theories of aqueous solvation of biological macromolecules is crucial to understanding their structure and function. This research will develop theories for macromolecular solvation and calculations that can then be used to study specific interactions of water and counterions with proteins. This theory can be used to predict t he solvation of a given structure; e.g., a crystal or NMR structure of a protein. Second, this theory of aqueous solvation of macromolecules will be incorporated into dynamics simulation algorithms. The final goal is incorporation of ionic strength effects into simulation methods. ***