Analyses of the folding sites of irregular ß-trefoil fold proteins through sequence-based techniques and Go-model simulations.

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. ß-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 ß-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 ß-trefoil proteins do not hinder the protein formation. Conserved hydrophobic residues on the ß5 strand are always the interaction center of packing between the conserved hydrophobic residues in both regular and irregular ß-trefoil proteins. CONCLUSIONS: We revealed that the ß5 strand plays an important role in ß-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.

A new technique for predicting intrinsically disordered regions based on average distance map constructed with inter-residue average distance statistics.

BACKGROUND: It had long been thought that a protein exhibits its specific function through its own specific 3D-structure under physiological conditions. However, subsequent research has shown that there are many proteins without specific 3D-structures under physiological conditions, so-called intrinsically disordered proteins (IDPs). This study presents a new technique for predicting intrinsically disordered regions in a protein, based on our average distance map (ADM) technique. The ADM technique was developed to predict compact regions or structural domains in a protein. In a protein containing partially disordered regions, a domain region is likely to be ordered, thus it is unlikely that a disordered region would be part of any domain. Therefore, the ADM technique is expected to also predict a disordered region between domains. RESULTS: The results of our new technique are comparable to the top three performing techniques in the community-wide CASP10 experiment. We further discuss the case of p53, a tumor-suppressor protein, which is the most significant protein among cell cycle regulatory proteins. This protein exhibits a disordered character as a monomer but an ordered character when two p53s form a dimer. CONCLUSION: Our technique can predict the location of an intrinsically disordered region in a protein with an accuracy comparable to the best techniques proposed so far. Furthermore, it can also predict a core region of IDPs forming definite 3D structures through interactions, such as dimerization. The technique in our study may also serve as a means of predicting a disordered region which would become an ordered structure when binding to another protein.