Discrete charge patterns, Coulomb correlations and interactions in protein solutions

– The effective Coulomb interaction between globular proteins is calculated as a function of monovalent salt concentration cs, by explicit Molecular Dynamics simulations of pairs of model proteins in the presence of microscopic co and counterions. For discrete charge patterns of monovalent sites on the surface, the resulting osmotic virial coefficient B2 is found to be a strikingly non-monotonic function of cs. The non-monotonicity follows from a subtle Coulomb correlation effect which is completely missed by conventional non-linear Poisson-Boltzmann theory and explains various experimental findings. A more fundamental understanding of the interactions between nano-sized biomolecules is critical to the long-term advance of modern biomedical research [1]. The best strategy for a predictive calculation is to study simple coarse-grained models where effects can be clearly separated and approximations can be systematically tested. While for micron-sized colloidal particles such coarse-grained models have led to a quantitative understanding of the effective interactions [2], the challenging question is how far this concept can be transferred to nano-particles. A particular issue is the aggregation and crystallization of globular proteins in solution, driven by their mutual interactions, including steric repulsion, van der Waals attraction, Coulombic interactions, hydration forces, hydrophobic attraction and depletion forces [2]. Most of these are effective interactions which depend sensitively on solution conditions. In particular Coulombic forces are functions of pH (which determines the total charge of the proteins) and of electrolyte concentration, which controls the Debye screening length λD, and hence the effective range of Coulombic interactions. This dependence on solution conditions is exploited in “salting-out” experiments where large salt concentrations are used to trigger protein crystallization, a crucial step towards the determination of their structure by X-ray diffraction [3]. While the forces acting between micro-sized colloidal particles are dominated by generic interactions, and are directly measurable by optical means [4–6], the interactions between globular proteins are highly specific at short range, and are less directly accessible.