Three key residues form a critical contact network in a protein folding transition state

Michele Vendruscolo, Emanuele Paci, Christopher M. Dobson () and Martin Karplus ()
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Michele Vendruscolo: Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford
Emanuele Paci: Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford
Christopher M. Dobson: Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford
Martin Karplus: Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford

Nature, 2001, vol. 409, issue 6820, 641-645

Abstract: Abstract Determining how a protein folds is a central problem in structural biology. The rate of folding of many proteins is determined by the transition state, so that a knowledge of its structure is essential for understanding the protein folding reaction. Here we use mutation measurements—which determine the role of individual residues in stabilizing the transition state1,2—as restraints in a Monte Carlo sampling procedure to determine the ensemble of structures that make up the transition state. We apply this approach to the experimental data for the 98-residue protein acylphosphatase3, and obtain a transition-state ensemble with the native-state topology and an average root-mean-square deviation of 6 Å from the native structure. Although about 20 residues with small positional fluctuations form the structural core of this transition state, the native-like contact network of only three of these residues is sufficient to determine the overall fold of the protein. This result reveals how a nucleation mechanism involving a small number of key residues can lead to folding of a polypeptide chain to its unique native-state structure.

Date: 2001
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DOI: 10.1038/35054591

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