On the Molecular Kinetics of Protein Crystal Nucleation and the Causes of Its Slowness: Peculiarities of the Protein–Protein Association

The rate of nucleation of crystals is the subject of extensive research, since it—together with the nucleation time—determines the number of crystals growing; in turn, their number is related to their size. Experimental studies show that, for biomolecular crystals, despite the required unusually high supersaturations, the nucleation process is distinctly slow. This slowness arises from the inherent peculiarity of the nucleation of such crystals. Therefore, a prerequisite for management of the crystallization process towards the desired outcome is the molecular level understanding of the nucleation mechanism. In this paper, analyzing the mechanisms behind the nucleation process of protein crystals, it is argued that the highly inhomogeneous molecule surface is the main reason for the slow crystal nucleation: only a few small patches on their surface are capable of forming crystalline bonds. Therefore, the partner proteins must not only be brought to encounter one another but must also find each other’s binding site. In turn, this requirement imposes a severe steric restriction on the association of protein molecules, which, however, is alleviated by a rotational-diffusional reorientation. This is why particular attention is paid to this aspect of the protein crystal nucleation process.