Feasibility in the inverse protein folding protocol

Methods for protein structure (3D)–sequence (1D) compatibility evaluation (threading) have been developed during the past decade. The protocol in which a sequence can recognize its compatible structure in the structural library (i.e., the fold recognition or the forward‐folding search) is available for the structure prediction of new proteins. However, the reverse protocol, in which a structure recognizes its homologous sequences among a sequence database, named the inverse‐folding search, is a more difficult application. In this study, we have investigated the feasibility of the latter approach. A structural library, composed of about 400 well‐resolved structures with mutually dissimilar sequences, was prepared, and 163 of them had remote homologs in the library. We examined whether they could correctly seek their homologs by both forward‐and inverse‐folding searches. The results showed that the inverse‐folding protocol is more effective than the forward‐folding protocol, once the reference states of the compatibility functions are appropriately adjusted. This adjustment only slightly affects the ability of the forward‐folding search. We noticed that the scoring, in which a given sequence is re‐mounted onto a structure according to the 3D–1D alignment determined by the dynamic programming method, is only effective in the forward‐folding protocol and not in the inverse‐folding protocol. Namely, the inverse‐folding search works significantly better with the score given by the 3D–1D alignment per se, rather than that obtained by the re‐mounting. The implications of these results are discussed.