Turn-directed folding dynamics of β-hairpin-forming de novo decapeptide Chignolin

• Published in: Physical chemistry chemical physics : PCCP 2012-09, Vol.14 (36), p.12442-12450
• Main Authors: ENEMARK, Søren, RAJAGOPALAN, Raj
• Format: Article
• Language: English
• Subjects: Chemistry; Exact sciences and technology; General and physical chemistry; Models, Molecular; Molecular Dynamics Simulation; Oligopeptides - chemistry; Protein Folding
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/c2cp40285h

Realistic mechanistic pictures of β-hairpin formation, offering valuable insights into some of the key early events in protein folding, are accessible through short designed polypeptides as they allow atomic-level scrutiny through simulations. Here, we present a detailed picture of the dynamics and mechanism of β-hairpin formation of Chignolin, a de novo decapeptide, using extensive, unbiased molecular dynamics simulations. The results provide clear evidence for turn-directed broken-zipper folding and reveal details of turn nucleation and cooperative progression of turn growth, hydrogen-bond formations, and eventual packing of the hydrophobic core. Further, we show that, rather than driving folding through hydrophobic collapse, cross-strand side-chain packing could in fact be rate-limiting as packing frustrations can delay formation of the native hydrophobic core prior to or during folding and even cause relatively long-living misfolded or partially folded states that may nucleate aggregative events in more complex situations. The results support the increasing evidence for turn-centric folding mechanisms for β-hairpin formation suggested recently for GB1 and Peptide 1 based on experiments and simulations but also point to the need for similar examinations of polypeptides with larger numbers of cross-strand hydrophobic residues.