Conformational preferences of a 14-residue fibrillogenic peptide from acetylcholinesterase

Ranjit Vijayan, Philip C. Biggin

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


A 14-residue fragment from near the C-terminus of the enzyme acetylcholinesterase (AChE) is believed to have a neurotoxic/neurotrophic effect acting via an unknown pathway. While the peptide is α-helical in the full-length enzyme, the structure and association mechanism of the fragment are unknown. Using multiple molecular dynamics simulations, starting from a tetrameric complex of the association domain of AChE and systematically disassembled subsets that include the peptide fragment, we show that the fragment is incapable of retaining its helicity in solution. Extensive replica exchange Monte Carlo folding and unfolding simulations in implicit solvent with capped and uncapped termini failed to converge to any consistent cluster of structures, suggesting that the fragment remains largely unstructured in solution under the conditions considered. Furthermore, extended molecular dynamics simulations of two steric zipper models show that the peptide is likely to form a zipper with antiparallel sheets and that peptides with mutations known to prevent fibril formation likely do so by interfering with this packing. The results demonstrate how the local environment of a peptide can stabilize a particular conformation.

Original languageEnglish
Pages (from-to)3678-3684
Number of pages7
Issue number17
Publication statusPublished - May 4 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry


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