Donut-shaped fingerprint in homologous polypeptide relationships—A topological feature related to pathogenic structural changes in conformational disease

Features of homologous relationship of proteins can provide us a general picture of protein universe, assist protein design and analysis, and further our comprehension of the evolution of organisms. Here we carried out a study of the evolution of protein molecules by investigating homologous relationships among residue segments. The motive was to identify detailed topological features of homologous relationships for short residue segments in the whole protein universe. Based on the data of a large number of non-redundant proteins, the universe of non-membrane polypeptide was analyzed by considering both residue mutations and structural conservation. By connecting homologous segments with edges, we obtained a homologous relationship network of the whole universe of short residue segments, which we named the graph of polypeptide relationships (GPR). Since the network is extremely complicated for topological transitions, to obtain an in-depth understanding, only subgraphs composed of vital nodes of the GPR were analyzed. Such analysis of vital subgraphs of the GPR revealed a donut-shaped fingerprint. Utilization of this topological feature revealed the switch sites (where the beginning of exposure of previously hidden “hot spots” of fibril-forming happens, in consequence a further opportunity for protein aggregation is provided; 188–202) of the conformational conversion of the normal α -helix-rich prion protein PrP C to the β -sheet-rich PrP Sc that is thought to be responsible for a group of fatal neurodegenerative diseases, transmissible spongiform encephalopathies. Efforts in analyzing other proteins related to various conformational diseases are also introduced.