The energy cost of polypeptide knot formation and its folding consequences

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Bustamante A.
Sotelo-Campos J.
Guerra D.G.
Floor M.
Wilson C.M.A.
Bustamante C.
Báez M.
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Nature Publishing Group
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Knots are natural topologies of chains. Yet, little is known about spontaneous knot formation in a polypeptide chain—an event that can potentially impair its folding—and about the effect of a knot on the stability and folding kinetics of a protein. Here we used optical tweezers to show that the free energy cost to form a trefoil knot in the denatured state of a polypeptide chain of 120 residues is 5.8 ± 1 kcal mol−1. Monte Carlo dynamics of random chains predict this value, indicating that the free energy cost of knot formation is of entropic origin. This cost is predicted to remain above 3 kcal mol−1 for denatured proteins as large as 900 residues. Therefore, we conclude that naturally knotted proteins cannot attain their knot randomly in the unfolded state but must pay the cost of knotting through contacts along their folding landscape.
This work was supported by Fondecyt 11110534 (to M.B.), 1151274 (to M.B.), 11130263 (to C.A.M.W.), Anillo 1107 (to M.B.), and Chile and Fondecyt 196–2013 (to D.G.G.) CONCYTEC, Perú. This research was partially supported by the supercomputing infrastructure of the NLHPC (ECM-02) at Universidad de Chile. A.B. was supported by Conicyt master fellowship 22121199. We gratefully acknowledge Professor Alexander Vologodskii from New York University for helpful comments and advice. Travel for C.B. to and from Chile and Peru was also partially supported by the Howard Hughes Medical Institute, NIH grant R01GM032543, and the U.S. Department of Energy Office of Basic Energy Sciences Nanomachine Program under contract no. DE-AC02-05CH11231.
Palabras clave
viral protein, polypeptide, kinetics, Monte Carlo analysis, peptide, polymer