Amyloidogenicity as a driving force for the formation of functional oligomers

Abstract

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OligoBinders: Bioengineered Soluble Amyloid-like Nanoparticles to Bind and Neutralize SARS-CoV-2

“… 39 Using this relationship, we proposed that if the linker between the amyloid and the globular sequences is short enough but still flexible, these molecules will not assemble into amyloid fibrils; instead, they would form oligomers with a defined and limited size. 40 …”

“…39 Using this relationship, we proposed that if the linker between the amyloid and the globular sequences is short enough but still flexible, these molecules will not assemble into amyloid fibrils; instead, they would form oligomers with a defined and limited size. 40 Using full-atom and coarse-grained targeted molecular dynamics together with rigid body simulations, we rationalized that fusing the 19-residue SAC of the Sup35 protein (residues 100−118) to a globular protein of ∼20 kDa through a short 5residue Gly/Ser (SGSGS) flexible linker would sterically hinder the formation of a fibrillar zipper and result in the assembly of amyloid-like oligomers of defined dimensions in which the embedded protein can remain in a folded conformation. 40 Subsequently, we demonstrated the accuracy of these predictions using dihydrofolate reductase (DHFR) as a model protein, with the Sup35-DHFR fusion forming enzymatically active oligomeric structures.…”

“…40 Using full-atom and coarse-grained targeted molecular dynamics together with rigid body simulations, we rationalized that fusing the 19-residue SAC of the Sup35 protein (residues 100−118) to a globular protein of ∼20 kDa through a short 5residue Gly/Ser (SGSGS) flexible linker would sterically hinder the formation of a fibrillar zipper and result in the assembly of amyloid-like oligomers of defined dimensions in which the embedded protein can remain in a folded conformation. 40 Subsequently, we demonstrated the accuracy of these predictions using dihydrofolate reductase (DHFR) as a model protein, with the Sup35-DHFR fusion forming enzymatically active oligomeric structures. 27 The above-described strategy permits the generation of tailored spherical nanoparticles for different purposes.…”

Multifunctional Amyloid Oligomeric Nanoparticles for Specific Cell Targeting and Drug Delivery

“…15 The model suggested that shortening the linker below this size limit would result in the formation of oligomers of defined size instead of the typical fibrils. 16,17 This might provide a unique opportunity to generate small protein-based nanoparticles decorated with al a carte globular protein functionalities.…”

“…Recently, using molecular and mesoscopic modeling, we were able to establish a theoretical relationship between the size of a globular domain and the length of the shortest linker that still allows the formation of infinite amyloid fibrils when fused to an amyloidogenic sequence . The model suggested that shortening the linker below this size limit would result in the formation of oligomers of defined size instead of the typical fibrils. , This might provide a unique opportunity to generate small protein-based nanoparticles decorated with à la carte globular protein functionalities.…”