Nucleation-condensation protein

Fig. 5. Protein folding. The unfolded polypeptide chain coUapses and assembles to form simple stmctural motifs such as -sheets and a-hehces by nucleation-condensation mechanisms involving the formation of hydrogen bonds and van der Waal s interactions. Small proteins (eg, chymotrypsin inhibitor 2) attain their final (tertiary) stmcture in this way. Larger proteins and multiple protein assembhes aggregate by recognition and docking of multiple domains (eg, -barrels, a-helix bundles), often displaying positive cooperativity. Many noncovalent interactions, including hydrogen bonding, van der Waal s and electrostatic interactions, and the hydrophobic effect are exploited to create the final, compact protein assembly. Further stmctural...

Depending on the protein, the free energy landscape differs as is illustrated in Fig. 6. For some two-state proteins, with an independently stable secondary structure, the diffusion-collision mechanism is preferred. Other proteins,for which the secondary structure is less stable on its own, fold cooperatively using the nucleation-condensation pathway. In all cases there is still two state behavior, because there is only one rate limiting barrier. 

N. Ferguson, R. Day, C. M. Johnson, M. D. Allen, V. Dagget, A. Fersht (2005) Simulation and experiment at high temperatures Ultrafast folding of a thermophilic protein by nucleation-condensation. J. Mol. Biol. 347, pp. 855-870... 

The nucleation condensation model of protein folding (Chapter 2)... 

The kinetic mechanism described above bears some resemblance to the framework and to the nucleation-condensation models." " In fact, the compact structure formed immediately after the early process of condensation is very similar to the molten globule concept proposed by Ptitsyn " in the case of all a and mainly a proteins, the molten globule does not suffer any other drastic changes, thus essentially following the two-state kinetics of many small proteins, " but in the case of a/jS and mainly jS proteins, the molten globule continues to evolve into a different shape as proposed in the... 

A key feature of the framework and nucleation-condensation models is the formation of secondary structure—which might or might not be coupled to the formation of tertiary structure—early in the folding process. It follows that a full description of the mechanism of protein folding also requires an understanding of the rules that stabilize molecular interactions in polypeptides. We consider these rules in Chapter 11. 

L. S. Itzhaki, D. E. Otzen, and A. R. Fersht, The structure of the transition state for folding of chymotrypsin inhibitor 2 analysed by protein engineering methods Evidence for a nucleation-condensation mechanism for protein folding. J. Mol. Biol. 254, 260-288 (1995). 

The threshold concentration of monomer that must be exceeded for any observable polymer formation in a self-assembling system. In the context of Oosawa s condensation-equilibrium model for protein polymerization, the cooperativity of nucleation and the intrinsic thermodynamic instability of nuclei contribute to the sudden onset of polymer formation as the monomer concentration reaches and exceeds the critical concentration. Condensation-equilibrium processes that exhibit critical concentration behavior in vitro include F-actin formation from G-actin, microtubule self-assembly from tubulin, and fibril formation from amyloid P protein. Critical concentration behavior will also occur in indefinite isodesmic polymerization reactions that involve a stable template. One example is the elongation of microtubules from centrosomes, basal bodies, or axonemes. 

The notion that folding proceeds from a condensed state rather than from a random coil state is somewhat heretical in an age dominated by the secondary structure nucleation point of view. However, the question has not been addressed experimentally, and the Dill model is in accord with the thermodynamics of unfolding for many globular proteins. 

Li, Y., Roberts, C.J. (2009) Lumry-Eyring nucleated-polymeiization model of protein aggregation kinetics. 2. Competing growth via condensation and chain polymerization. J Phys Chem S, 113 (19), 7020-7032. 

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