Theoretical and computational studies of hydrophobic and hydrophilic hydration: Towards a molecular description of the hydration of proteins

The unique balance of forces underlying biological processes--such as protein folding, aggregation, molecular recognition, and the formation of biological membranes--owes its origin in large part to the surrounding aqueous medium. A quantitative description of fundamental noncovalent interactions, in particular hydrophobic and electrostatic interactions at molecular-scale separations, requires an accurate description of water structure. Thus, the primary goals of our research are to understand the role of water in mediating interactions between molecules and to incorporate this understanding into molecular theories for calculating water-mediated interactions.; We have developed a molecular model of hydrophobic interactions that uses methods of information theory to relate hydrophobic effects to the density fluctuations in liquid water. This model provides a quantitative description of small-molecule hydration thermodynamics, as well as insights into the entropies of unfolding globular proteins.; For larger molecular solutes, we relate the inhomogeneous water structure in their vicinity to their hydration thermodynamics. We find that the water structure in the vicinity of nonpolar solutes is only locally sensitive to the molecular details of the solute. Water structures predicted using this observation are used to study the association of two neopentane molecules and the conformational equilibria of n-pentane molecule.; We have also studied the hydration of a model molecular ionic solute, a tetramethylammonium ion, over a wide range of charge states of the solute. We find that, although the charge dependence of the ion hydration free energy is quadratic, negative ions are more favorably hydrated compared to positive ions. Moreover, this asymmetry of hydration can be reconciled by considering the differences in water organization surrounding positive and negative ions. We have also developed methods for predicting water structure surrounding molecular ions and relating this water structure to their hydration thermodynamics.; The major conclusion reached from this research is that the key to calculating the hydration thermodynamics is an accurate microscopic description of water structure surrounding the solutes of interest. Finally, our studies show the power of molecular theories in describing hydration phenomena, such as the asymmetry of ion hydration, that can not be accounted for by macroscopic theories, except in an empirical or ad hoc manner.