Anomalies in the ionic properties of serum albumin

The documented difference in the isoionic points of native and unfolded serum albumins is revisited with computational methods. Good agreement between calculated and measured ΔpIs is found, with the molecular origin appearing to reside in a diverse set of carboxyl group titrations. Although histidine ionisation plays only a minor role in bringing about the ΔpI, the identification of three histidine residues with low computed pKas (around pH 5) suggests an explanation for the mismatch between experimentally derived group pKas and the pI of the native protein. Computed electrostatic properties (including pI) of native serum albumins are compared with a set of 178 nonenzyme proteins. We find that the degree of interdigitation of positive and negative charges is extreme for serum albumin, and discuss the relationship to protein solubility and pH-dependent structural transitions. © 2005 Wiley-Liss, Inc.