Most eukaryotic proteins contain more than one independently folding domain. Since the local concentration of domains is high, how do natural proteins avoid misfolding? Our single molecule studies of the folding and misfolding of multidomain proteins suggest that the early folding events of multidomain proteins are much more intricate than previously thought. The single molecule data suggest that ~50% of the total population form transient non-native species.
Since co-translational folding is likely to be important to prevent misfolding particularly for multidomain proteins, we are now investigating the folding of multidomain proteins on stalled ribosomes. We conclude that individual domains can fold close to the ribosome, certainly before the following domain has been translated and that this will prevent inter-domain misfolding.