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.
Highlights
The formation of contacts between pairs of residues in an unfolded polypeptide chain is one of the earliest steps in in vitro protein folding and is considered to determine the so-called protein folding speed limit [1]
In studies of protein folding evidence exists for early compaction in the unfolded state, it is unclear whether these compact conformations contain specific secondary structures or whether compaction is a non-specific hydrophobic-driven effect
Loop closure of poly-GS peptides is characterized by combining fluorescence correlation spectroscopy with atomistic molecular dynamics simulation
Summary
The formation of contacts between pairs of residues in an unfolded polypeptide chain is one of the earliest steps in in vitro protein folding and is considered to determine the so-called protein folding speed limit [1]. The molecules studied here are glycine-serine (GS) based peptides Due to their high chain flexibility, their solubility and the absence of a stable folded structure [23,25,27,30,52] these have been shown to be valuable model systems for studying end-to-end contact formation in ‘‘unstructured’’ polypeptide chains under native conditions, providing insight highly relevant to our fundamental understanding of the very first steps of protein
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