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Protein folding

Matching speed and locality

Nature volume 392, pages 761–763 (1998)Cite this article

The experimentally observed folding times for different proteins can differ by more than nine orders of magnitude — from tens of microseconds to hours. Can these be rationalized by models for generic proteins? Unfortunately, theoreticians have not yet reached a consensus on the main determining factor that gives rise to this tremendous diversity in folding rates. In this month's Journal of Molecular Biology, Plaxco, Simons and Baker1 provide much-needed systematic comparisons between theory and experiment. By statistical analysis of the correlations between measured folding rates and the various determinants proposed by theoreticians, they have identified a main structural factor that governs folding speed for a set of non-homologous, single-domain proteins that fold with essentially two-state kinetics. Remarkably, they find this to be the average sequence separation between contacting residues in the native state, normalized by the length of the protein chain — an extremely simple measure that they call relative contact order.

This statistical study confirms a general picture that has been emerging from recent experiments — that stronger local interactions, especially those conducive to helix formation, tend to lead to faster folding2. Nanosecond laser temperature-jump experiments on short peptides show that folding of a β-hairpin at room temperature is about 30 times slower than formation of an α-helix3. Moreover, in a set of protein engineering experiments4, folding rate decreased with increasing length of an inserted poly-glycine loop. Local guidance seems to be critical in reducing the time that is needed for a protein to find its native structure.

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Figure 1: Theoretical proteins, adapted from the cubic lattice models of Abkevich et al.8.
Figure 2: Two proteins in the data set analysed by Plaxco et al.1.

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  1. the Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143-1204, California, USA

    Hue Sun Chan

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Chan, H. Matching speed and locality. Nature 392, 761–763 (1998). https://doi.org/10.1038/33808

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