title: Effects of interactions with the GroEL cavity on protein folding rates.
abstract: Encapsulation of proteins in chaperonins is an important mechanism by which the cell prevents the accumulation of misfolded species in the cytosol. However, results from theory and simulation for repulsive cavities appear to be inconsistent with recent experimental results showing, if anything, a slowdown in folding rate for encapsulated Rhodanese. We study the folding of Rhodanese in GroEL, using coarse-grained molecular simulations of the complete system including chaperonin and substrate protein. We find that, by approximating the substrate:GroEL interactions as repulsive, we obtain a strong acceleration in rate of between one and two orders of magnitude; a similar result is obtained by representing the chaperonin as a simple spherical cavity. Remarkably, however, we find that using a carefully parameterized, sequence-based potential to capture specific residue-residue interactions between Rhodanese and the GroEL cavity walls induces a very strong reduction of the folding rates. The effect of the interactions is large enough to completely offset the effects of confinement, such that folding in some cases can be even slower than that of the unconfined protein. The origin of the slowdown appears to be stabilization--relative to repulsive confinement--of the unfolded state through binding to the cavity walls, rather than a reduction of the diffusion coefficient along the folding coordinate.
authors.affiliation: University of Cambridge, Department of Chemistry, Cambridge, United Kingdom.
authors.forename: Anshul
authors.initials: A
authors.lastname: Sirur
authors.forename: Robert B
authors.initials: RB
authors.lastname: Best
mesh_terms: D000595:Amino Acid Sequence; D018834:Chaperonin 60 / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D013884:Thiosulfate Sulfurtransferase / Q000737:chemistry / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; D013884:Thiosulfate Sulfurtransferase