Dynamics of the minimally frustrated helices determine the hierarchical folding of small helical proteins.
In this paper we aim at determining the key residues of small helical proteins in order to build up reduced models of the folding dynamics. We start by arguing that the folding process can be dissected into concurrent fast and slow dynamics. The fast events are the quasiautonomous coil-to-helix transitions occurring in the minimally frustrated initiation sites of folding in the early stages of the process. The slow processes consist in the docking of the fluctuating helices formed in these critical sites. We show that a neural network devised to predict native secondary structures from sequence can be used to estimate the probabilities of formation of these helical traits as they are embedded in the protein. The resulting probabilities are shown to correlate well with the experimental helicities measured in the same isolated peptides. The relevance of this finding to the hierarchical character of folding is confirmed within the framework of a diffusion-collision-like mechanism. We demonstrate that thermodynamic and topological features of these critical helices allow accurate estimation of the folding times of five proteins that have been kinetically studied. This suggests that these critical helices determine the fundamental events of the whole folding process. A remarkable feature of our model is that not all of the native helices are eligible as critical helices, whereas the whole set of the native helices has been used so far in other reconstructions of the folding mechanism. This stresses that the minimally frustrated helices of these helical proteins comprise the minimal set of determinants of the folding process.
Compiani
M
M
Department of Chemical Sciences, University of Camerino, Camerino, Italy.
Capriotti
E
E
Casadio
R
R
D001665:Binding Sites; D001703:Biophysics / Q000379:methods*; D004058:Diffusion; D019277:Entropy; D015233:Models, Statistical; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics