Computational backbone mutagenesis of Aβ peptides: Probing the role of backbone hydrogen bonds in aggregation

摘要

Using REMD and united atom implicit solvent model we examine the role of backbone hydrogen bonds (HBs) in Aβ aggregation. The importance of HBs appears to depend on the aggregation stage. The backbone HBs have little effect on the stability of Aβ dimers or on their aggregation interface. The HBs also do not play a critical role in initial binding of Aβ peptides to the amyloid fibril. Their elimination does not change the continuous character of Aβ binding nor its temperature. However, cancellation of HBs forming between incoming Aβ peptides and the fibril disrupts the locked fibril-like states in the bound peptides. Without the support of HBs bound Aβ peptides form few long β-strands on the fibril edge. As a result the deletion of peptide-fibril HBs is expected to impede fibril growth. As for the peptides bound to Aβ fibril the deletion of interpeptide HBs reduces the β propensity in the dimers making them less competent for amyloid assembly. These simulation findings together with the backbone mutagenesis experiments suggest that a viable strategy for arresting fibril growth is the disruption of interpeptide HBs.