Assessing Accumulated Solvent Near a Macromolecular Solute by Preferential Interaction Coefficients

Abstract

Biological macromolecules are often studied in mixed solvents. To understand cosolvent-macromolecule interactions, the preferential interaction coefficient, Gamma(3), may help determine surface solvent compositions. Gamma(3) measures the amounts of water, B(1), and cosolvent, B(3), within the "local domain," the (possibly far-reaching) region surrounding the macromolecule where the solvent is non-bulk-like. The local domain's boundary is, however, vague and it is unclear which molecules are counted in B(i). It is useful to explore a simple model system to make B(i) more concrete and to understand which aspects of the surface solvent distribution, rho(x), are sampled by Gamma(3). We performed computer simulations on a two-dimensional (2D) system consisting of a hard-wall solute (the macromolecule) in a mixed solvent (hard disks of different radii). We simultaneously calculated Gamma(3) and rho(x). We found that 1) in practice, the local domain's boundary is demarked by the outer limit of the first cosolvent (not water) layer; B(i) mainly counts the solvent near the macromolecule; 2) assuming B(1) to count only the waters within the first water layer is a poor approximation; 3) when determining B(1) and B(3), water and cosolvent molecules must be counted from the same region of space. We speculate that these 2D results may serve as a first-order approximation for the dominant contributions to Gamma(3) even in three dimensions, so long as the cosolvent is not strongly excluded from the macromolecular surface and there is no significant long-ranged solvent structure.

Recent Applications of Kirkwood–Buff Theory to Biological Systems

“…Tang and Bloomfield have used grand canonical Monte Carlo simulations of model systems to evaluate C 23 [165]. While they did not specifically use KB theory, the type of analysis performed is equivalent to Eq.…”

Proteins in Mixed Solvents: A Molecular-Level Perspective

“…To date, statistical mechanical models of preferential binding have only been developed for interactions of ions with charged cylinders [18], [19] and for interactions of twodimensional, "hard circles" with a linear interface [20], both far too simple to be generally applied to protein-cosolvent systems. Other explicit mixed solvent simulations of proteins and amino acids have been performed [21], [22], [23], [24], [25], but these studies did not compute thermodynamic quantities A simulation cell containing RNase T1 (center, green spheres) solvated by water (thin blue lines) and urea (red spheres).…”

Estimating hydration changes upon biomolecular reactions from osmotic stress, high pressure, and preferential hydration experiments

“…To do so, osmolytes (such as glycerol and polyethylene glycol, known as protein stabilisers) are added to the system (4-6). Because protein-stabilizing osmolytes, preferentially excluded from protein surfaces (11)(12)(13)(14)(15), are not accessible to cavities, grooves, channels, or pockets formed by biomolecules, these regions are subject to osmotic stress (4)(5)(6). Osmotic stress and the accompanied change of water activity modulate the equilibrium of the process, and the number of waters adsorbed upon the reaction in the absence of osmolytes are enumerated by measuring the change of equilibrium constant with respect to osmotic pressure (4)(5)(6).…”

“…In spite of its popularity, the validity of OSA has been debated (6,(11)(12)(13)(14)(15). Timasheff (11) pointed out that a cosolvent cannot be both excluded and inert at the same time, because exclusion requires a positive free energy change.…”