Intermolecular forces in the process of heat aggregation of globular proteins and the problem of correlation between aggregation and denaturation phenomena

The heat aggregation of globular proteins depends on a coupled coagulation and exchange reaction which may be differentiated with respect to its relative proportions by specific inhibition of aggregation and by degradation analysis. In general, the coagulation by weak intermolecular forces exceeds the covalent exchange reaction (disulfide and lanthionine bonds). Decreasing net charge further diminishes the covalent aggregation and at the same time the rate of denaturation, so that under isoelectric conditions as the limiting case, the particles agglomerate with conservation of their native state. At high electrostatic potential denaturation is the precursor of aggregation. Inhibition of aggregation is produced by formaldehyde, weak protic solvents, ionic detergents, and urea, etc.; only formaldehyde seems to react without denaturation, leading to the conclusion that hydrogen bonds cause the coagulation of the native particles while aggregation by hydrophobic interactions presupposes (partial) denaturation. Ion‐pair bonds may participate in the aggregation at extreme pH values. As regards the tertiary and quaternary structure, one may conclude that in the native state polar groups must be situated in the periphery of the molecule while the nonpolar side chains cluster together in the center of the globular molecule. This result verifies Kendrew's principle of tertiary structure formation derived from solid‐state x‐ray analysis for the molecule in solution and is also compatible with the specific dissociation‐association phenomena observed in the case of the quaternary structure.