The response of Greek key proteins to changes in connectivity depends on the nature of their secondary structure.

What governs the balance between connectivity and topology in regulating the mechanism of protein folding? We use circular permutation to vary the order of the helices in the all-α Greek key protein FADD (Fas-associated death domain) to investigate this question. Unlike all-β Greek key proteins, where changes in the order of secondary structure cause a shift in the folding nucleus, the position of the nucleus in FADD is unchanged, even when permutation reduces the complexity significantly. We suggest that this is because local helical contacts are so dominant that permutation has little effect on the entropic cost of forming the folding nucleus whereas, in all-β Greek key proteins, all interactions in the nucleus are long range. Thus, the type of secondary structure modulates the sensitivity of proteins to changes in connectivity.This work was supported by the Wellcome Trust (WT095195) (J.C), Engineering and Physical Sciences Research Council (UK) Grant EP/J016764/1 (D.D.S.) and an Engineering and Physical Sciences Research Council (UK) studentship (K.R.K.). J.C. is a Wellcome Trust Senior Research fellow.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S0022283615002168#