Interdiscip Sci Comput Life Sci (2011) 3: 290–307 DOI: 10.1007/s12539-011-0104-7 Electrolytes in Biomolecular Systems Studied with the 3D-RISM/RISM Theory Yutaka MARUYAMA 1 , Norio YOSHIDA 1,2 , Fumio HIRATA 1,2∗ 1 (Department of Theoretical Molecular Science, Institute for Molecular Science, Okazaki 444-8585, Japan) 2 (Department of Functional Molecular Science, Graduate University for Advanced Studies, Okazaki 444-8585, Japan) Received 15 March 2011 / Revised 11 April 2011 / Accepted 13 April 2011 Abstract: We reviewed our recent studies on the molecular recognition and stability of biomolecules in aqueous so- lutions, which have been carried out based on the statistical mechanics of molecular liquids, or the 3D-RISM/RISM theory. A special stress is put on roles of electrolytes in determining the stability of biomolecules. Key words: 3D-RISM theory, molecular recognition, electrolyte solution. 1 Introduction There are two physicochemical processes in living cells, which are essential to maintain their life, “self- organization (SO)” and “molecular recognition (MR)”. Typical examples of “self organization” occurring in cells are folding of protein and membrane formation. In the former, a protein folds into a specific three- dimensional structure from a random coil conformation, provided a particular amino-acid sequence and thermo- dynamic conditions such as temperature, pressure, and ion concentrations. In the latter, constituents of mem- brane, such as phospholipids and cholesterols, are self- assembled to form a membrane-wall, given proper ther- modynamic conditions. “Molecular recognition” processes are seen every- where in cells whenever a biomolecule such as protein and DNA works as molecular machines: enzyme, ion channels, oxygen carrier, and so forth. For example, in order for an enzyme to function as a biocatalyst, it has to bind or “recognize” substrate molecules at its active-site or “reaction pocket” (Michaelis, 1913). In order for an ion channel to permeate ions from one side of cell membrane to the other, it must accommodate the ions inside its pore. The MR process can be de- fined as a molecular process in which one or a few guest molecules are bound in high probability at a particular site, a cleft or a cavity, of a host molecule in a particular orientation. Since most of protein and DNA exhibits “function- ality” in their native conformation, the SO process is ∗ Corresponding author. E-mail: hirata@ims.ac.jp a structural basis for the MR process. Not only that, structural fluctuation of protein and DNA around its native states controls sometimes MR processes as is ex- emplified by gating mechanism of ion channels and in- duced fitting of a ligand by a receptor protein. On the other hand, in many cases, water molecules and ions recognized by protein and DNA play a crucial role as a “building block” in order to stabilize the biomolecules in solutions. In such a sense, the SO and MR pro- cesses work cooperatively, not independently, in many elementary processes in life phenomena. It is important to realize that both SO and MR are molecular processes governed by “thermodynamic” laws, not just by “mechanical” laws, in which solvent environment or solution conditions play an essential role. The processes can be viewed as a “chemical re- action” in solutions, the equilibrium constant of which is governed by the free energy difference between reac- tants and products: in the case of protein folding, the reactant and product are native and denatured states of protein, respectively, while in the case of molecular recognition, those are bound and unbound states of a ligand-receptor complex. In this article, we review recent progress in our study on conformational stability and molecular recognition concerning protein and DNA in electrolyte solutions, taking solvent and salt effects on those phenomena into account. A special stress is put on roles played by elec- trolytes in determining structural stability of biopoly- mers, since the paper is devoted to Prof. Blum, a great scientist and a pioneer in the integral equation theory of electrolyte solutions (Blum and Torruella, 1972; Blum, 1972 and 1973; Vericat et al., 1983). Professor Blum has developed analytical methods to solve the Ornstein-