Comparative studies of the folding of homologous domains have proved to be valuable in understanding protein folding.1,2 Two principal questions are asked in such studies: the first concerns the pathway; which elements of structure fold early and which fold late? The second is a question of mechanism; it has been suggested that there is a continuum of mechanisms,3 from strictly framework, diffusion collision mechanisms characterised by polarised transition states,4,5 to pure nucleation condensation mechanisms, characterised by diffuse transition states with strictly concomitant formation of secondary and tertiary structure.6 Although in a few protein families, the folding pathway does not appear to be conserved (e.g. protein G and protein L7) in many protein families the transition states of homologous proteins are remarkably similar; even where the transition state of one protein is much more structured, the general structural features of the transition state are maintained. This has been observed, for instance, in the immunity proteins Im7 and Im9, which have 60% sequence identity,8 and in the immunoglobulin-like (Ig-like) proteins including the Ig domain from human titin, TI I27, and a fibronectin type III domain from human tenascin, TNfn3, which have no significant sequence identity, although they share a common fold.9–11 Folding mechanisms within a fold can vary significantly between homologous proteins, even where the transition states have similarly structured regions. In the homeodomain superfamily, for instance, folding mechanisms range from a strict framework/diffusion collision mechanism (engrailed homeodomain) to pure nucleation condensation (hTRF1).3 In this case, the mechanism is apparently determined by secondary structure (helical) propensity. Thus, studies of the folding of related proteins suggest that both topology and the nature of the secondary structure content have a role in determining how a protein folds.12