Cytoplasmic folding, mis-folding, and early stages of aggregation

Author:

Samuel Russell Premila P.ORCID,Rickard Meredith M.ORCID,Boob MayankORCID,Gruebele MartinORCID,Pogorelov Taras V.ORCID

Abstract

AbstractWe examine how cellular interactions in an all-atom model of theHomo sapienscytoplasm influence the early folding events of Protein B (PB), a three-helix bundle protein. While PB is known to fold duringin vitrosimulations in three microseconds, all three initially unfolded PB copies in our cytoplasm model never completely reached their native topology across our 31 microsecond simulation. We were able to capture initial formation of all three helices and a compact topology similar to the native state. Sticking interactions between PB and surrounding macromolecules, as well as other unfolded PBs, became competitive with PB folding. Interaction between PB copies seeded beta-strand formation, modeling initial events of protein aggregation. Finally, the fold-switching potential of PB related GA domains has been explored in previous studies, and the sticking and crowding in our model thus initiates sampling of helix/sheet structural plasticity of PB.

Publisher

Cold Spring Harbor Laboratory

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