Toshiko Ichiye MCB 98-08116 1. TECHNICAL ABSTRACT Water plays an important role in the structure and function of proteins such as in folding, enzymatic activity, and interactions with other molecules. However, water is a complex solvent whose properties are still not completely understood. The interaction of water with proteins is particularly complex because they are large molecules with a variety of functional groups and no regular structure. Thus, the development of theories of aqueous solvation for proteins is crucial to understanding their structure and function. The long-term goals of this study are 1) to develop fast, accurate treatments of solvent effects in computer simulations of biological macromolecules and 2) to understand the nature of protein solvation, including phenomena such as the hydrophobic effect and ionic solvation. Specific aims are: 1) to incorporate PI's new model of water into computer simulations of proteins, 2) to apply PI's macromolecular integral equation theory to proteins, and 3) to investigate aqueous solvation of proteins via PI's nonlinear continuum theory and simulations. The main methods are statistical mechanical theory and molecular dynamics computer simulations. In the first aim, the new soft, sticky dipole (SSD) model of water previously developed by PI's group will be implemented for computer simulations of proteins. The SSD model is a considerable advance over the three-site models commonly used for biological simulations because it has better structural, dielectrical and dynamical properties and yet is seven times faster in Monte Carlo and three to four times faster in molecular dynamics simulations. An SSD water molecule is composed of a Lennard-Jones sphere with a point dipole and a tetrahedral "sticky" potential mimicking hydrogen bonding interactions. The energy parameters are simply given in terms of the position and orientation of a water molecule, whereas the three-site models are given in terms of the positions of the oxygen and the two hydrogens. The SSD model will be implemented in CHARMM, a molecular mechanics computer program, and tested in molecular dynamics simulations of proteins. In addition, further testing of the solvation properties and including explicit electronic polarization are proposed. In the second aim, a theory for solvation of globular molecules previously developed by PI's group will be implemented for proteins. This model allows the replacement of explicit solvent in computer simulations with an implicit model that accurately describes the important features of aqueous solvation with less computer time. The theory models the molecular nature of solvation using statistical mechanical integral equation theories, which have been highly successful in predicting the structure of simple liquids. Specifically, an approximate Ornstein-Zernike equation theory with a modified hypernetted chain closure is used to predict the distribution of water molecule positions and orientations around a solute. The important features of this approach are the retention of the full three-dimensional distribution and the separation of the density and orientational parts of the distribution. The theory predicts molecular properties such as hydrogen bonding, which cannot be obtained by simple continuum models, and yet maintains the correct macroscopic limit electrostatics. The theory will be used to predict solvation energies of proteins. Finally, a theory of ionic solvation previously developed in PI's group will be used to analyze molecular dynamics simulations of proteins and simple model systems. This will increase the understanding of water structure at the protein-water interface; in particular, the orientational structure, which determines the polarization energy of the solvent. The theory is a quasi-continuum approach based on the works of Onsager and Kirkwood that predicts the orientation of water molecules but does not include specific molecular interactions. It goes beyond simple Born th eories of solvation by including non-linear effects such as dielectric saturation and, with a recent modification, electrostriction. Also, further extensions of the theory will be investigated, such as including molecular effects heuristically and increasing the predictive capabilities for complex solutes such as proteins. 2. Non-technical Water plays an important role in the structure and function of proteins such as in folding, enzymatic activity, and interactions with other molecules. However, water is a complex solvent whose properties are still not completely understood. The interaction of water with proteins is particularly complex because they are large molecules with a variety of functional groups and no regular structure. Thus, the development of theories of aqueous solvation for proteins is crucial to understanding their structure and function. The long-term goals of this study are 1) to develop fast, accurate treatments of solvent effects in computer simulations of biological macromolecules and 2) to understand the nature of protein solvation, including phenomena such as the hydrophobic effect and ionic solvation. The main methods are statistical mechanical theory and molecular dynamics computer simulations. The specific aims are to implement and extend models/theories previously developed by PI's group which include 1) a soft, sticky dipole (SSD) model of water 2) a theory for solvation of globular molecules, and 3) a theory of ionic solvation. The SSD model is a considerable advance over the three-site models commonly used for biological simulations because it has better structural, dielectrical and dynamical properties and yet is seven times faster in Monte Carlo and three to four times faster in molecular dynamics simulations. It will be tested for computer simulations of proteins. The solvation model allows the replacement of explicit solvent in computer simulations with an implicit model that, in less computer time, describes molecular properties such as hydroge n bonding and yet maintains the correct macroscopic limit electrostatics. The ionic theory is to analyze molecular dynamics simulations of proteins and simple model systems. This will increase our understanding of water structure at the protein-water interface; in particular, the orientational structure, which determines the polarization energy of the solvent.
