Effect of the air–water interface on the conformation of amyloid beta

Abstract

It has long been recognised that liquid interfaces, such as the air-water interface (AWI) can enhance formation of protein fibrils. This makes liquid interfaces attractive templates for fibril formation but fully realising this requires knowledge of protein behaviour at interfaces, which is currently lacking. To address this molecular dynamics simulation is used to investigate fragments of amyloid beta, a model fibril forming protein, at the air-water interface. At the air-water interface the enrichment of aggregation-prone helical conformations provides a mechanism for the enhancement of fibrillation at interfaces. The conformational ensemble at the air-water interface was also considerably reduced compared to bulk solution, due to the tendency of hydrophobic side chains partitioning into the air restricting the range of conformations. Little overlap between the conformational ensembles at the AWI and in bulk solution was found, suggesting that AWI induces the formation of different set of structures compared to bulk solution. The smaller Aβ (16)(17)(18)(19)(20)(21)(22) and fragments show an increase in the propensity for ordered secondary structure at the air-water interface but with a increased propensity for turn over other motifs, illustrating the importance of intra-protein interactions for stabilising helical and extended conformations.

The amyloidogenic peptide amyloid beta(16-22) displays facet dependent conformation on metal surfaces

“…For cos φ < 0, which corresponds to the trans-state the probability is lower for the Au111 compared to the other systems with P (cos φ) going to zero at cos φ = −1. This enhancement of cis-conformers has been seen in previous studies of Aβ (16)(17)(18)(19)(20)(21)(22) on interfaces 47,80 and of the diphenylalanine dipeptide 81 at the air-water interface.…”

“…Notably N clusters is smaller for all surfaces compared to bulk solution, due to the binding of specific residues to the surfaces (Figure 1(c)) which limits the possible conformations, which has been seen in previous simulations of intrinsically disordered proteins on surfaces 50,80 . This is particularly noticable for the Au111 surface due to the strong binding of the two Phe residues to the surface.…”

The Influences of Sulphation, Salt Type, and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans

“…The and dihedral angles for each linkage type were combined into a single dihedral offset function, ( ) [ 73 ], making it easier to capture deviations in both dihedral angles and across a GAG chain via a single descriptor: …”

The Role of Cyclodextrins against Interface-Induced Denaturation in Pharmaceutical Formulations: A Molecular Dynamics Approach

“… 5 − 9 It is generally believed that the migration of proteins to the interface with air, as well as oil–water interfaces, where the exposure of the hydrophobic core is promoted, is responsible for the observed loss of stability. 10 − 13 The formation of ice during freezing has also been found to be detrimental for proteins, 14 − 17 but in this case, there still is no widespread agreement in the literature about the underlying mechanism. While it was first thought that adsorption onto the ice surface may be key for destabilization, 14 , 18 recent experimental and simulation results indicate that direct interaction with the interface is not needed.…”

“…Among the possible sources of denaturation, the air–water and ice–water interfaces are commonly encountered during the production and storage of therapeutic proteins. The formation of a large air–water surface during mixing and shaking has often been shown to promote unfolding and aggregation. − It is generally believed that the migration of proteins to the interface with air, as well as oil–water interfaces, where the exposure of the hydrophobic core is promoted, is responsible for the observed loss of stability. − The formation of ice during freezing has also been found to be detrimental for proteins, − but in this case, there still is no widespread agreement in the literature about the underlying mechanism. While it was first thought that adsorption onto the ice surface may be key for destabilization, , recent experimental and simulation results indicate that direct interaction with the interface is not needed. − In contrast, pressure build-up, concentration gradients and pH shifts, accumulation of gas bubbles, , or cold denaturation phenomena were proposed as possible routes of denaturation upon ice formation.…”