Hydrogen-Bond Driven Loop-Closure Kinetics in Unfolded Polypeptide Chains

Isabella Daidone, Hannes Neuweiler, Sören Doose, Markus Sauer and Jeremy C Smith

PLOS Computational Biology, 2010, vol. 6, issue 1, 1-9

Abstract: Characterization of the length dependence of end-to-end loop-closure kinetics in unfolded polypeptide chains provides an understanding of early steps in protein folding. Here, loop-closure in poly-glycine-serine peptides is investigated by combining single-molecule fluorescence spectroscopy with molecular dynamics simulation. For chains containing more than 10 peptide bonds loop-closing rate constants on the 20–100 nanosecond time range exhibit a power-law length dependence. However, this scaling breaks down for shorter peptides, which exhibit slower kinetics arising from a perturbation induced by the dye reporter system used in the experimental setup. The loop-closure kinetics in the longer peptides is found to be determined by the formation of intra-peptide hydrogen bonds and transient β-sheet structure, that accelerate the search for contacts among residues distant in sequence relative to the case of a polypeptide chain in which hydrogen bonds cannot form. Hydrogen-bond-driven polypeptide-chain collapse in unfolded peptides under physiological conditions found here is not only consistent with hierarchical models of protein folding, that highlights the importance of secondary structure formation early in the folding process, but is also shown to speed up the search for productive folding events.Author Summary: In studies of protein folding evidence exists for early compaction in the unfolded state, although it is unclear whether these compact conformations contain specific secondary structures (through hydrophilic interactions) or whether compaction is a non-specific hydrophobic-driven effect. Here we combine single-molecule fluorescence spectroscopy and molecular dynamics simulation to demonstrate peptide hydrogen-bond-driven polypeptide-chain collapse involving secondary structure formation as the key process in the early stage of folding. Partial structuring in unfolded polypeptide chains is shown to lead to faster contact formation kinetics than would be expected if the unfolded state were populated by featureless random-coils.

Date: 2010
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1000645

DOI: 10.1371/journal.pcbi.1000645

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