Protein-solvent interactions.

The central importance of solvent interactions in stabilization of specific protein structure has long been recognized. Decades ago, Tanford and Kirkwood treated in detail the interaction of charges with solvent, and they showed how desolvation/burial of charges upon protein folding was an important factor in stability.1 The influence of their model, with further elaborations, can still be seen in much subsequent work on protein electrostatics and implicit solvent models. A little later, Kauzmann provided a seminal insight into the second major “theme” in protein-solvent interaction: The hydrophobic effect and how burial of hydrophobic amino acid side chains could stabilize proteins and play a role in determining their structure.2 The view that hydrophobicity is the major contributor to protein stability is widely held,3 although current studies of solvation recognize the importance of other types of solvent-protein interaction, including van der Waals, polar, charged, ionic, and hydrogen bonding interactions. The view of solvation as a stabilizing force was further expanded to include the possibility that solvent interactions play a role in specifying structure and function: that water is in effect the “21st amino acid”. The field of experimental and theoretical studies, even for this rather specialized topic, is now too vast to be covered in any single review. We have selected four topics for discussion in this review: peptide-water interactions, new experimental probes of protein hydration, new solvent models for long protein-solvent simulations, and thermal hysteresis proteins. The selection was guided by the theme of this issue: protein folding. The rationale for discussing peptides is that the effect of solvent on conformations/nascent folding is best understood in these systems. Peptides have long been used as more experimentally and computationally tractable test systems for studying protein-solvent interactions and developing simulation methods. Thus, much of what is known about the specific and quantitative effects of solvent on proteins is derived from peptide studies. This applies particularly to * Telephone: 215-573-3506. Fax: 215-898-4217. E-mail: sharpk@ mail.med.upenn.edu. Ninad Prabhu received an M.Sc. in Chemistry from the Indian Institute of Technology, Bombay, in 1991. He did his doctoral thesis with Professor Montgomery Pettitt in the area of peptide simulations, receiving his Ph.D. in Chemistry from the University of Houston in 1998. He is currently a research scientist in the Department of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine.