3 years ago

Mechanistic Origin of the Combined Effect of Surfaces and Mechanical Agitation on Amyloid Formation

Mechanistic Origin of the Combined Effect of Surfaces and Mechanical Agitation on Amyloid Formation
Claudio Colombo, Lenka Rezabkova, Raffaele Ferrari, Paolo Arosio, Fulvio Grigolato
Interactions between proteins and surfaces in combination with hydrodynamic flow and mechanical agitation can often trigger the conversion of soluble peptides and proteins into aggregates, including amyloid fibrils. Despite the extensive literature on the empirical effects of surfaces and mechanical forces on the formation of amyloids, the molecular details of the mechanisms underlying this behavior are still elusive. This limitation is, in part, due to the complex reaction network underlying the formation of amyloids, where several microscopic reactions of nucleation and growth can occur both at the interfaces and in bulk. In this work, we design a high-throughput assay based on nanoparticles and we apply a chemical kinetic platform to analyze the mechanisms underlying the effect of surfaces and mechanical forces on the formation of amyloid fibrils from human insulin under physiological conditions. By considering a variety of polymeric nanoparticles with different surface properties we explore a broad range of repulsive and attractive interactions between insulin and surfaces. Our analysis shows that hydrophobic interfaces induce the formation of amyloid fibrils by specifically promoting the primary heterogeneous nucleation rate. In contrast, mechanical forces accelerate the formation of amyloid fibrils by favoring mass transport and further amplify the number of fibrils by promoting fragmentation events. Thus, surfaces and agitation have a combined effect on the kinetics of protein aggregation observed at the macroscopic level but, individually, they each affect distinct microscopic reaction steps: the presence of interfaces generates primary nucleation events of fibril formation, which is then amplified by mechanical forces. These results suggest that the inhibition of surface-induced heterogeneous nucleation should be considered a primary target to suppress aggregation and explain why in many systems the simultaneous presence of surfaces and hydrodynamic flow enhances protein aggregation.

Publisher URL: http://dx.doi.org/10.1021/acsnano.7b05895

DOI: 10.1021/acsnano.7b05895

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