Native aggregation as a cause of origin of temporary cellular structures needed for all forms of cellular activity, signaling and transformations

The role of the dynamic hydrophobic protein phase in the life of the cell has not been studied at all. It is unknown in the equations of cell physiology. At present, one can discuss the significance of this X-factor only in terms of very general regularities based on simple physical principles. For instance, it is obvious that the appearance of the hydrophobic phase in a cell will cause the redistribution of all hydrophobic compounds including ATP [8]. The redistribution of hydrophobic substances between the cell and the medium will also begin.

However, the redistribution of substances is triggered not only by the appearance of the temporary hydrophobic phase, but also by the desorption of water from protein surfaces. As secondary structures start to form, the adsorbed water will become free and the "bad" solvent will become "good". This will lead to a rapid invasion of small solute molecules into the areas that were previously occupied by adsorbed water. If we take into account the rapid rate of formation of secondary structures ([7], Lecture 9), it becomes obvious that during the fast destruction of the ordered water structure, sharp concentration gradients of such substances will appear. In the case of ions, everywhere in the cell, in microvolumes, significant diffusional potentials will appear that may prove to be one cause of the appearance of molten globules. Significant concentration gradients of dissolved substances can also appear when the ordered water layers are restored, as the rate of their restoration will also be determined by the high rate of disassembly of secondary structures in activated proteins.

It is obvious that during the course of native aggregation the density and rigidity of the protein matrix will increase owing to a rise in the number of interprotein contacts. This provides even more difficulties for models of cell function regulation that base their mechanisms on the free diffusion of substances in the cell, since with an increase of protein matrix density the significance of diffusional processes will decrease.

If we return to the cell protoreaction, it can be concluded with certainty that the hypothesis of native aggregation has managed to explain the rise of viscosity and turbidity of the cytoplasm (Fig. 1) as well as the increase of volume of the cell hydrophobic phase. From the proposed mechanism it is clear that the changes discussed will occur synchronously, as the key link among all these changes is the structural readjustment of the same key proteins.

The cornerstone of the hypothesis of native aggregation is the generation in proteins of temporary secondary structures that can interact selectively with secondary structures in the same or other proteins. The nonspecific reaction of cells, which was studied by Nasonov's school, turns out in reality to comprise myriads of specific protein-protein interactions. Since native aggregation is directed by active secondary protein structures, it proves to be completely under genetic control, so the dogma of Anfinsen [53] formulated for the folded polypeptide chain can be extended by incorporating native aggregation into its sphere of application.

I am very grateful to Paul Agutter, James Clegg, Ilya Digel, Laurent Jaeken, José Neira and Richard Wiggins for valuable critical comments on this article. I also appreciate Leonid Pevzner's assistance in preparation of this paper.