NONNATIVE LOCAL INTERACTIONS IN PROTEIN-FOLDING AND STABILITY - INTRODUCING A HELICAL TENDENCY IN THE ALL BETA-SHEET ALPHA-SPECTRIN SH3 DOMAIN

The relative importance of secondary structure interactions versus ter tiary interactions for stabilising and guiding the folding process is a matter for discussion. Phenomenological models of protein folding as sign an important role to local contacts in protein folding and stabil ity. On the other hand, simplistic lattice simulations find that secon dary structure is mainly the product of protein compaction and that op timisation of folding speed seems to require small contributions of lo cal contacts to the stability of the folded state. To examine tile ext ent to which secondary structure propensities influence protein foldin g and stability, we have designed mutations that introduce a strong na n-native helical propensity in the first 19 residues of the alpha-spec trin SH3 domain. The mutant proteins have the same three-dimensional s tructure as the wild-type, but they are less stable and have less co-o perative folding transitions. There seems to be a relationship between the non-native helical propensity and the compaction of the denatured state. This suggests that in the denatured ensemble under native cond itions there is a significant proportion of compact structures with no n-native secondary structures. Our results demonstrate that non-local interactions can overcome strong non-native secondary structure propen sities and, more important, that optimisation of folding speed and co- operativity requires the latter to be relatively small. (C) 1997 Acade mic Press Limited.