Replica exchange molecular dynamics simulation of cross-fibrillation of IAPP and PrP106-126

Abstract

Aggregation of proteins into amyloid is the central hallmark of a number of protein diseases. Most studies were carried out on the aggregation between proteins of similar species. However, it was observed that some patients with certain protein disease can easily acquire another unrelated protein disease. As such, it is also important to examine aggregation between proteins of different species. Usually aggregation between proteins of the same species can be attributed to the similarity between their respective amino acid sequences. In this article, we were motivated by an experimental study of aggregation between amylin (Islet Amyloid Polypeptide, IAPP) and prion106-126 (PrP106-126) fragment (JACS, 2013, 135, 13582-9). It was found that the two non-homologous peptides can aggregate quickly to form fibrils in the presence of negatively charged lipid bilayer. We attempted to elucidate the molecular mechanism of the early stage of dimerization of these two peptides through extensive replica exchange molecular dynamics simulations. Conformations consisting of various degrees of β-sheets structures, both intra-chain and inter-chain, were found in the simulations. The conformations of the aggregated complex are very diverse, which suggests that the cross-species fibrils formed between the two proteins are highly polymorphic. The driving forces are mainly hydrophobic interactions, including aromatic-aliphatic interactions. The palindromic region of PrP106-126 and SNNFGAIL region of IAPP were found to play important roles in the interaction. Our study sheds insight into the exciting research of protein cross-fibrillation. Proteins 2016; 84:1134-1146. © 2016 Wiley Periodicals, Inc.

Hetero-oligomeric Amyloid Assembly and Mechanism: Prion Fragment PrP(106–126) Catalyzes the Islet Amyloid Polypeptide β-Hairpin

“…The formation of this extended conformation is also consistent with the observed α-helix to β-sheet conversion observed by CD and is in full agreement with our MD simulations. Previous molecular dynamics simulations on hIAPP and PrP 106–126 mixtures in the literature have suggested PrP 106–126 interacts primarily with the 20–29 region of hIAPP . However, this region contains proline at positions 25, 28, and 29 for rIAPP, which should inhibit interaction with PrP 106–126 , and our results suggest it is only marginally involved in the PrP/IAPP interaction, if at all.…”

“…Previous molecular dynamics simulations of PrP 106–126 and hIAPP hetero-oligomerization indicated that hydrophobic interaction is one of the primary driving forces of coaggregation, with particular interaction occurring between PrP 106–126 and the 20–29 aggregation-prone region of hIAPP . In order to experimentally probe this result, we have looked at the interaction of PrP 106–126 with both hIAPP and rIAPP, since rat IAPP contains several proline substitutions within the region in question (Scheme ).…”

“…IAPP and the critical amyloidogenic and neurotoxic fragment of PrP (PrP 106–126 ) − have been of particular interest as a model of amyloid interaction, as they exhibit little to no sequence homology, and yet mixtures may still produce heterogeneous fibrils and aggregate more aggressively than each individual peptide by itself. , Understanding the nature of this process would provide key insight into the broader driving forces of amyloid species acting as prions. The primary sequences of IAPP and PrP 106–126 are given in Scheme .…”

“…The primary sequences of IAPP and PrP 106–126 are given in Scheme . Molecular modeling studies have suggested that hetero-oligomers of hIAPP and PrP 106–126 are primarily driven by hydrophobic interactions and that the amyloidogenic region of human IAPP (hIAPP), 20–29, acts as a significant association site with PrP 106–126 . In order to probe oligomer formation in vitro and to elucidate more about the structural changes that occur to both species in their early oligomeric states, we consider not only the interaction of hIAPP with PrP 106–126 but also the interaction of non-amyloidogenic rat IAPP with PrP 106–126 .…”

On the Conformational Dynamics of β-Amyloid Forming Peptides: A Computational Perspective

“…The single layer showed better stability than the double layer model in most of the cases, which implies that cross-seeding, rather than a combination of different species of protofibrils may occur in alternate fibril elongation. Another extensive REMD simulation study focused on the cross-seeding dimerization of amyloid peptides, IAPP and prion 106-126 fragment (Chua et al, 2016). The highly diverse aggregating complex suggests the formation of highly polymorphic crossspecies fibrils or oligomers between the two peptides.…”