A classical nonpolarizable force field is presented for the simulation of aqueous alkali halide solutions (MX), where M = Li+, Na+, K+, Rb+, Cs+ and X = F−, Cl−, Br−, I−, and their interactions with biomolecules. The models are specifically designed to reproduce the experimental Kirkwood-Buff integrals, and thereby the solution salt activities, as a function of salt concentration. Additionally, we demonstrate that these models reasonably reproduce other experimental properties including ion diffusion constants, dielectric decrements, and the excess heats of mixing. The parameters are developed by considering the properties of aqueous NaX and MCl solutions using a previously established model for NaCl. Transferability of the parameters to other salts is then established by the successful simulation of additional aqueous salt solutions, KI and CsBr, not originally included in the parameterization procedure.

Most cellular processes occur in systems containing a variety of components many of which are open to material exchange. However, computer simulations of biological systems are almost exclusively performed in systems closed to material exchange. In principle, the behavior of biomolecules in open and closed systems will be different. Here, we provide a rigorous framework for the analysis of experimental and simulation data concerning open and closed multicomponent systems using the Kirkwood-Buff (KB) theory of solutions. The results are illustrated using computer simulations for various concentrations of the solutes Gly, Gly2 and Gly3 in both open and closed systems, and in the absence or presence of NaCl as a cosolvent. In addition, KB theory is used to help rationalize the aggregation properties of the solutes. Here one observes that the picture of solute association described by the KB integrals, which are directly related to the solution thermodynamics, and that provided by more physical clustering approaches are different. It is argued that the combination of KB theory and simulation data provides a simple and powerful tool for the analysis of complex multicomponent open and closed systems.

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An analysis of the effect of a cosolvent on the association of a solute in solution using the Kirkwood-Buff theory of solutions is presented. The approach builds on the previous results of Ben-Naim by extending the range of applicability to include any number of components at finite concentrations in both closed and semiopen systems. The derived expressions, which are exact, provide a foundation for the analysis and rationalization of cosolvent effects on molecular and biomolecular equilibria including protein association, aggregation, and cellular crowding. A slightly different view of cellular crowding is subsequently obtained. In particular, it is observed that the addition of large cosolvents still favors the associated form even when traditional excluded volume effects are absent.

A new classical nonpolarizable force field, KBFF20, for the simulation of peptides and proteins is presented. The force field relies heavily on the use of Kirkwood−Buff theory to provide a comparison of simulated and experimental Kirkwood−Buff integrals for solutes containing the functional groups common in proteins, thus ensuring intermolecular interactions that provide a good balance between the peptide−peptide, peptide−solvent, and solvent−solvent distributions observed in solution mixtures. In this way, it differs significantly from other biomolecular force fields. Further development and testing of the intermolecular potentials are presented here. Subsequently, rotational potentials for the ϕ/ψ and χ dihedral degrees of freedom are obtained by analysis of the Protein Data Bank, followed by small modifications to provide a reasonable balance between simulated and observed α and β percentages for small peptides. This, the first of two articles, describes in detail the philosophy and development behind KBFF20.