Sequence dependent aggregation of peptides and fibril formation

Abstract

Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientations for hydrophobic contacts. A significant heterogeneity is observed in the aggregate structures and in the thermodynamics of aggregation for systems of different HP sequences and different number of peptides. Fibril-like ordered aggregates are found for several sequences that contain the common HPH pattern while other sequences may form helix bundles or disordered aggregates. A wide variation of the aggregation transition temperatures among sequences, even among those of the same hydrophobic fraction, indicates that not all sequences undergo aggregation at a presumable physiological temperature. The transition is found to be the most cooperative for sequences forming fibril-like structures. For a fibril-prone sequence, it is shown that fibril formation follows the nucleation and growth mechanism. Interestingly, a binary mixture of peptides of an aggregation-prone and a non-aggregation-prone sequence shows association and conversion of the latter to the fibrillar structure. Our study highlights the role of sequence in selecting fibril-like aggregates and also the impact of structural template on fibril formation by peptides of unrelated sequences.

Viscoelastic properties of wheat gluten in a molecular dynamics study

“…However, if the contact is due to the bb interactions, its strength is doubled. Doubling the depth of the L-J potential for bb contacts is consistent with the earlier literature ndings [29]. If criteria for creation of a given type of contact are met, the attractive part of the potential is turned on at r min in a quasi-adiabatically fashion (during 10 τ ).…”

Finite-size scaling analysis of protein droplet formation

“…It is worth noting that sequences with alternating hydrophobic and polar residues tend to have a high β-sheet propensity [36,37]. The biophysical model used in our present calculations cannot describe β-sheet formation, due to the lack of hydrogen bonding.…”

Disordered peptide chains in an α-C-based coarse-grained model

“…The energy parameter for each type of the ss contacts is the same. This, together with allowing for the formation of hydrophobic-polar ss contacts, distinguishes our model from the simple ,,HP" models, 40 where such contacts either have reduced strength or are not allowed to arise. Thus, even though our model cannot capture the details of all possible interactions (for instance, between the π electrons on the faces of aromatic rings and cations), our models allows for them statistically.…”

“…Another difference is that the establishment of contacts between the α-C atoms is governed not only by their mutual distance but also by the expected directionality of the side chains as derived from the positions of the α-C atoms. In this respect, we borrow from several Monte Carlo studies pertaining to the natively structured proteins [37][38][39] and fibril formation 40 but provide a molecular dynamics implementation of this concept. It should be pointed out that, unlike most other coarse-grained approaches, the nature and characteristics of a given contact may be time-dependent because an interaction between, say, two sidechains may switch to that between one sidechain and the other backbone.…”