UvA-DARE (Digital Academic Repository) Elucidating the Locking Mechanism of Peptides onto Growing Amyloid Fibrils through Transition Path Sampling

Abstract

Elucidating the locking mechanism of peptides onto growing amyloid fibrils through transition path sampling Schor, M.; Vreede, J.; Bolhuis, P.G. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. ABSTRACT We investigate the molecular mechanism of monomer addition to a growing amyloid fibril composed of the main amyloidogenic region from the insulin peptide hormone, the LVEALYL heptapeptide. Applying transition path sampling in combination with reaction coordinate analysis reveals that the transition from a docked peptide to a locked, fully incorporated peptide can occur in two ways. Both routes involve the formation of backbone hydrogen bonds between the three central amino acids of the attaching peptide and the fibril, as well as a reorientation of the central Glu side chain of the locking peptide toward the interface between two b-sheets forming the fibril. The mechanisms differ in the sequence of events. We also conclude that proper docking is important for correct alignment of the peptide with the fibril, as alternative pathways result in misfolding