  Tuning of protein surface charge is a fundamental mechanism in biological
systems. Protein charge is regulated in a physiological context by pH and
interaction with counterions. We report on charge inversion and the related
reentrant condensation in solutions of globular proteins with different
multivalent metal cations. In particular, we focus on the changes in phase
behavior and charge regulation due to pH effects caused by hydrolysis of metal
ions. For several proteins and metal salts, charge inversion as measured by
electrophoretic light scattering is found to be a universal phenomenon, the
extent of which is dependent on the specific protein-salt combination.
Reentrant phase diagrams show a much narrower phase-separated regime for acidic
salts such as AlCl3 and FeCl3 compared to neutral salts such as YCl3 or LaCl3 .
The differences between acidic and neutral salts can be explained by the
interplay of pH effects and binding of the multivalent counterions. The
experimental findings are reproduced with good agreement by an analytical model
for protein charging taking into account ion condensation, metal ion hydrolysis
and interaction with charged amino acid side chains on the protein surface.
Finally, the relationship of charge inversion and reentrant condensation is
discussed, suggesting that pH variation in combination with multivalent cations
provides control over both attractive and repulsive interactions between
proteins.
