Abstract
Background The details of the folding mechanisms have not yet been fully understood for many proteins, and it is believed that the information on the folding mechanism of a protein is encoded in its amino acid sequence. beta-trefoil proteins are known to have the same 3D scaffold, namely, a three-fold symmetric scaffold, despite the proteins' low sequence identity among superfamilies. In this study, we extract an initial folding unit from the amino acid sequences of irregular beta-trefoil proteins by constructing an average distance map (ADM) and utilizing inter-residue average distance statistics to determine the relative contact frequencies for residue pairs in terms of F values. We compare our sequence-based prediction results with the packing between hydrophobic residues in native 3D structures and a Go-model simulation. Results The ADM and F-value analyses predict that the N-terminal and C-terminal regions are compact and that the hydrophobic residues at the central region can be regarded as an interaction center with other residues. These results correspond well to those of the Go-model simulations. Moreover, our results indicate that the irregular parts in the beta-trefoil proteins do not hinder the protein formation. Conserved hydrophobic residues on the beta 5 strand are always the interaction center of packing between the conserved hydrophobic residues in both regular and irregular beta-trefoil proteins. Conclusions We revealed that the beta 5 strand plays an important role in beta-trefoil protein structure construction. The sequence-based methods used in this study can extract the protein folding information from only amino acid sequence data, and well corresponded to 3D structure-based Go-model simulation and available experimental results.
