Distribution of tightened end fragments of globular proteins statisticallymatches that of topohydrophobic positions: towards an efficient punctuation of protein folding?

Using a set of 372 proteins representative of a variety of 56 distinct glob ular folds, a statistical correlation was observed between two recently rev ealed features of protein structures: tightened end fragments or 'closed lo ops', i.e. sequence fragments that are able in three-dimensional (3D) space to nearly close their ends (a current parameter of polymer physics), and ' topohydrophobic positions', i.e. positions always occupied in 3D space by s trong hydrophobic amino acids for all members of a fold family. Indeed in s equence space, the distribution of preferred lengths for tightened end frag ments and that for topohydrophobic separation match. In addition to this st atistically significant similarity, the extremities of these 'closed loops' may be preferentially occupied by topohydrophobic positions, as observed o n a random sample of various folds. This observation may be of special inte rest for sequence comparison of distantly related proteins. It is also impo rtant for the ab initio prediction of protein folds, considering the remark able topological properties of topohydrophobic positions and their paramoun t importance within folding nuclei. Consequently, topohydrophobic positions locking the 'closed loops' belong to the deep cores of protein domains and might have a key role in the folding process.