Long-lived mesoscopic clusters of a dense protein liquid have been found in concentrated solutions of several proteins, including lysozyme, hemoglobin, insulin, and others. These clusters are a necessary kinetic intermediate for the formation of solid aggregates of native and misfolded protein molecules; these aggregates underlie physiological and pathological processes, and laboratory and industrial procedures. We have proposed a novel physicochemical mechanism, whereby the clusters consist of a strongly non-equilibrium mixture of single protein molecules and long-lived complexes of proteins, possibly involving other solutes. The puzzling mesoscopic size of the clusters is determined by the lifetime of the complexes and their diffusion constant. We have predicted and observed a number of interesting kinetic and thermodynamic behaviors that are associated with the mesoscopic clusters. These behaviors include (a) a crossover to long-range density fluctuations at high concentrations; (b) a universal, diffusion-like scaling of the autocorrelation function of light scattered of the protein solution; (c) non-trivial dependencies of the cluster size and volume fraction on the protein concentration in the solution. I will discuss the detailed mechanisms of complex formation and highlight the significance of the hydration interaction and domain swapping with regard to the ubiquity of the clusters and their sensitivity to the chemical composition of the solvent. Our findings suggest novel ways to control protein aggregation.

Biography of Vassiliy Lubchenko:
Dr. Lubchenko's research interests include strongly disordered and non-equilibrium systems, with specific applications to materials science, molecular electronics, and biophysics.