On the Microscopic Mechanism of Mesoscopic Aggregation in Protein Solutions



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Mesoscopic clusters of protein-rich fluid are observed in solutions of several proteins. The molecular origin and thermodynamics underlying the formation of the clusters are poorly understood. Here we test the “complexation” scenario of cluster formation, in which the clusters represent a spatially heterogeneous mixture of protein and protein containing complexes. Two separate aspects of this microscopic picture are addressed in the present work. On the one hand, we have developed a novel coarse-grained model that accounts for anisotropy of the Coulomb component of protein-protein interaction. Solvent-screened Coulomb interactions between protein molecules are approximated at the Debye-Huckel level, with corrections to account for polarization at the protein-solvent interface. We establish that transient complexes formed by folded molecules of the protein lysozyme are too short-lived to give rise to mesoscopic clusters; thus complex formation in lysozyme must involve partial unfolding of individual protein molecules. On the other hand, we develop a complete framework to treat nucleation in fluid mixtures, in the presence of chemical conversion between components of the mixture. We establish an expression for the coordinate-dependent pressure in the Landau-Ginzburg functional theory, which is applicable to mixtures and non-equilibrium situations. We discover that in contrast with nucleation in mixtures with conserved amounts of components, finite-sized metastable phases can be kinetically stabilized in the presence of chemical conversion between the components. Clusters of such metastable minority phases will grow indefinitely, upon reaching a certain critical size; the growth is eventually halted by a mechanical instability. On approach to equilibrium, Ostwald-like ripening is predicted to take place, but with a distinct time-dependence of the cluster size from the Lifshitz-Slyozov-Wagner theory. The present results provide substantial support for the complexation scenario for the formation of the mesoscopic clusters.



Mesoscopic, Clusters, Proteins, Anisotropy, Metastable


Portions of this document appear in: Chan, Ho Yin, Vladimir Lankevich, Peter G. Vekilov, and Vassiliy Lubchenko. "Anisotropy of the Coulomb interaction between folded proteins: consequences for mesoscopic aggregation of lysozyme." Biophysical journal 102, no. 8 (2012): 1934-1943. https://doi.org/10.1016/j.bpj.2012.03.025