Protein Engineering, Vol. 14, No. 10, 723-733,
October 2001
© 2001 Oxford University Press
The building block folding model and the kinetics of protein folding
1 Intramural Research Support Program—SAIC Laboratory of Experimental and Computational Biology, NCI-Frederick, Bldg 469, Rm 151, Frederick, MD 21702, USA and 2 Sackler Institute of Molecular Medicine, Department of Human Genetics, Medical School, Tel Aviv University,Tel Aviv 69978, Israel
Here we show that qualitatively, the building blocks folding model accounts for three-state versus the two-state protein folding. Additionally, it is consistent with the faster versus slower folding rates of the two-state proteins. Specifically, we illustrate that the building blocks size, their mode of associations in the native structure, the number of ways they can combinatorially assemble, their population times and the way they are split in the iterative, step-by-step structural dissection which yields the anatomy trees, explain a broad range of folding rates. We further show that proteins with similar general topologies may have different folding pathways, and hence different folding rates. On the other hand, the effect of mutations resembles that of changes in conditions, shifting the population times and hence the energy landscapes. Hence, together with the secondary structure type and the extent of local versus non-local interactions, a coherent, consistent rationale for folding kinetics can be outlined, in agreement with experimental results. Given the native structure of a protein, these guidelines enable a qualitative prediction of the folding kinetics. We further describe these in the context of the protein folding energy landscape. Quantitatively, in principle, the diffusion–collision model for the building block association can be used. However, the folding rates of the building blocks and traps in their formation and association, need to be considered.
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