Protein folding

Protein Folding/Misfolding. We have identified a protein folding intermediate, characterized as near-native and desolvated. We observe both on- and off-pathway folding events on a 300 microsecond timescale. We can describe a folding trajectory beginning with fast formation of hydrogen bonds and native-like folds with concomitant desolvation, after which the protein diffusively searches for a compact folded state. This may have significant consequences to protein misfolding and aggregation since a desolvated folding intermediate is likely key to aggregation and amyloidosis.

Figure 1. Graphical representation of water and oxygen accessibility in the native (N) and the near-native intermediate (I) states of CaM, based upon solvent isotope shifts (Δδ*(H2O)) and paramagnetic shifts (Δδ*(O2)) associated with 3-fluorophenylalanine probes in the protein interior. Site I refers to a folding intermediate which is similar to the recently theorized dry molten globule state. The protein is expanded, yet desolvated in the interior. Our belief is that this state is key to misfolding and amyloidosis. Sites having higher water or oxygen accessibility are shown with spheres having a larger radius and darker shade of blue or pink, respectively. Note that residues F12 and F141 exhibit solvent isotope shifts, which are too small to be observed using the current scale. The depiction of the near native intermediate structural model was constructed by slightly modifying the known native CaM structure to correspond to a slightly larger hydrodynamic radius.

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