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Effect of the air-water interface on the conformation of amyloid beta.

ABSTRACT: It has long been recognized that liquid interfaces, such as the air-water interface (AWI), can enhance the formation of protein fibrils. This makes liquid interfaces attractive templates for fibril formation but fully realizing this requires knowledge of protein behavior 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 the bulk solution was found, suggesting that AWI induces the formation of a different set of structures compared to bulk solution. The smaller Aβ(16-22) and Aβ(25-35) fragments show an increase in the propensity for an 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 stabilizing helical and extended conformations.

SUBMITTER: Samantray S

PROVIDER: S-EPMC7863683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:At the air/buffer solution interface the kinetics of adsorption of amyloid beta peptide, Abeta(1-42), whose bulk concentration (submicromolar) is more than 2 orders of magnitude lower than that typically used in other in vitro aggregation studies, has been studied using a Langmuir-Blodgett trough. The pressure-time curves exhibit a lag phase, wherein the surface pressure essentially remains at zero, and a rising phase, corresponding to the Abeta adsorption at the interface. The duration of the lag phase was found to be highly dependent on both the Abeta bulk concentration and the solution temperature. A large activation energy (62.2 +/- 4.1 KJ/mol) was determined and the apparent adsorption rate constant was found to be linearly dependent on the Abeta bulk concentration. Attenuated total reflection-IR spectra of the adsorbed Abeta transferred to a solid substrate and circular dichroism measurements of Abeta in the solution layer near the interface reveal that the natively unstructured Abeta in the bulk undergo a conformation change (folding) to mainly the alpha-helical structure. The results suggest that, prior to the adsorption step, an equilibrium between Abeta conformations is established within the subsurface. The kinetic equation derived from this model confirms that the overall Abeta adsorption is kinetically controlled and the apparent rate constant is proportional to the Abeta bulk concentration. This model also indicates that interfaces such as cell membranes and lipid bilayers may facilitate Abeta aggregation/ fibrillation by providing a thin hydrophobic layer adjacent to the interface for the initial A/beta conformation change (misfolding) and accumulation. Such a preconcentration effect offers a plausible explanation of the fact that Abeta fibrillation occurs in vivo at nanomolar concentrations. Another important biological implication from our work is that Abeta misfolding may occur before its adsorption onto a cell membrane. This general kinetic model should also find applications in adsorption studies of other types of biomolecules whose overall kinetics exhibits a lag phase that is dependent on the bulk concentration of the adsorbate.

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Effect of the air-water interface on the conformation of amyloid beta.

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