Hydrophobic Effects and Modeling of Biophysical Aqueous Solution Interfaces Lawrence R. Pratt* ,† and Andrew Pohorille* ,‡ Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, and NASA, Ames Research Center, Exobiology Branch, Moffett Field, California 94035 Received March 7, 2002 Contents 1. Introduction 2671 1.1. Definition of Subject Reviewed 2671 1.2. Orientation and Preliminaries 2672 1.2.1. Macroscopic Conceptualizations and Microscopic Progress 2672 1.2.2. Some Basic Results from Statistical Thermodynamics 2673 1.2.3. Molecular Model of Hydrophobic Temperature Dependences 2674 2. Aqueous Interfaces 2675 2.1. Water at ‘Inert’ Walls 2675 2.1.1. Model Hydrophobe and Water at Inert Walls 2677 2.2. Vapor-Liquid Water Interface 2677 2.2.1. Validation of Simulation Models for Water Liquid-Vapor Coexistence 2678 2.3. Nonpolar Liquid-Liquid Water Interfaces 2679 2.4. Recent Experimental Probes of Aqueous Interface Structure 2680 2.4.1. Surface Nonlinear Optics Experiments 2680 2.4.2. X-ray Reflectivity 2681 2.5. Water-Membrane Interfaces 2681 3. Solute Molecules at Aqueous Interfaces 2681 3.1. Interfacial Activity and Orientational Preferences of Small Solutes 2682 3.1.1. Simple Amphiphilic Molecules at Interfaces 2682 3.1.2. Distribution of Hydrophobic Species through Interfaces 2682 3.1.3. Activity of Polar Molecules at Interfaces between Water and Organic Liquids or Membranes 2682 3.1.4. Biological Significance of Solute Distributions in Water-Membrane Systems 2683 3.1.5. Orientations and Conformations of Amino Acids and Dipeptides at Aqueous Interfaces 2684 4. Peptides and Peptide Folding at Interfaces and insertion of Peptides into Membranes 2684 4.1. Interfacial Folding of Peptides and Protein Fragments 2684 4.2. Hydrophobic Effects and Insertion of Peptides into Membranes 2687 5. Conclusions 2688 6. Acknowledgment 2688 7. References 2688 1. Introduction As hydration contributions to stability of macro- molecular assemblies in aqueous solution, hydropho- bic effects are virtually universally acknowledged. Hydrophobic effects are widely believed to stabilize folded structures of globular proteins. 1,2 More straight- forwardly, hydrophobic contributions drive the for- mation of micelles and bilayer membranes. 3 These topics are frequently central to discussions of the origin of life. 4-6 It has long been obvious that hydrophobic effects can exhibit an impressive variety of expression and context. In molecular terms, the conceptual chain from the solubility of inert gases to the formation of micelles and membranes to the structures of soluble proteins is extended and branched. Small hydropho- bic solutes in water and extended interfaces of water with organic solutions, membranes, or biological macromolecules form opposite ends of a spectrum of possibilities. The connections between these limiting cases have not been reviewed recently, and the role of hydrophobic effects in mediating phenomena at aqueous interfaces has received relatively little at- tention compared to other aspects of hydrophobic behavior. The past decade has seen compelling progress in the molecular theory of the most primitive of hydro- phobic effects, those of submacromolecular scale. 7,8 At the same time, substantial theory and modeling results have accumulated on hydrophobic effects associated with solution surfaces and macromol- ecules. This article reviews the latter results from the perspective of the recent progress with small molecule problems. Our goal is to assist consolidation of small-molecule-scale theories of hydrophobic effects with concepts of hydrophobic effects at a supermo- lecular scale. 1.1. Definition of Subject Reviewed Specifically, we review theory and modeling results on surfaces of liquid water contacting materials of biophysical interest. Our plan is to start with the simplest instances of water in contact with hydro- * To whom correspondence should be addressed. † Los Alamos National Laboratory. ‡ NASA, Ames Research Center. 2671 Chem. Rev. 2002, 102, 2671-2692 10.1021/cr000692+ CCC: $39.75 © 2002 American Chemical Society Published on Web 07/16/2002