Phase behavior of aqueous solutions containing dipolar proteins from second-order perturbation theory

Due to the interplay of Coulombic repulsion and attractive dipolar and van der Waals interactions, solutions of globular proteins display a rich variety of phase behavior featuring fluid-fluid and fluid-solid transitions that strongly depend on solution pH and salt concentration. Using a simple model for charge, dispersion and dipole-related contributions to the interprotein potential, we calculate phase diagrams for protein solutions within the framework of second-order perturbation theory. For each phase, we determine the Helmholtz energy as the sum of a hard-sphere reference term and a perturbation term that reflects both the electrostatic and dispersion interactions. Dipolar effects can induce fluid-fluid phase separation or crystallization even in the absence of any significant dispersion attraction. Because dissolved electrolytes screen the charge-charge repulsion more strongly than the dipolar attraction, the ionic strength dependence of the potential of mean force can feature a minimum at intermediate ionic strengths offering an explanation for the observed nonmonotonic dependence of the phase behavior on salt concentration. Inclusion of correlations between charge-dipole and dipole-dipole interactions is essential for a reliable calculation of phase diagrams for systems containing charged dipolar proteins and colloids.