The foldon universe: A survey of structural similarity and self-recognition of independently folding units

We have identified independently folding units, so called 'foldons', from non-homologous proteins representing different folds. We applied simple statistical arguments in order to estimate the size of the foldon universe required to construct all foldable proteins. Various alignment procedures yield about 2600 foldons in the natural protein universe but this estimate is shown to be rather sensitive to the chosen cut-off value for structural similarity. We showed that foldon matching-modelling can reproduce the major part of the main chain of several proteins with a structural similarity measure Q-score of about 0.4 and an r.m.s. error of about 5 Å, although the accuracy of structure prediction has been limited so far by the small size of foldon data set. The prediction score may be increased if one uses the set of protein fragments with optimized sequence-structure relationships, in other works, minimally frustrated segments. To quantify the degree of frustration of the structures of foldons from our database, we searched for those foldons which recognize their own sequence and structure upon threading. As a result we found that about half of the foldons from our data set recognize themselves as the best choice upon threading and therefore are individually minimally frustrated. We showed that there is a close connection between the Q-score of self recognition and the relative foldability (Θ) of the folding units. Foldons having high Q-score and Θ values are expected to be formed in the early phase of the folding process and be observed as stable intermediates under appropriate experimental conditions.