Multiscale analysis of structurally conserved motifs

Abstract

AbstractThis work develops a generic framework to perform a multiscale structural analysis of two structures (homologous proteins, conformations) undergoing conformational changes. Practically, given a seed structural alignment, we identify structural motifs with a hierarchical structure, characterized by three unique properties. First, the hierarchical structure sheds light on the trade-off between size and flexibility. Second, motifs can be combined to perform an overall comparison of the input structures in terms of combined RMSD - an improvement over the classical least RMSD. Third, motifs can be used to seed iterative aligners, and to design hybrid sequence-structure profile HMM characterizing protein families.From the methods standpoint, our framework is reminiscent from the bootstrap and combines concepts from rigidity analysis (distance difference matrices), graph theory, computational geometry (space filling diagrams), and topology (topological persistence).On challenging cases (class II fusion proteins, flexible molecules) we illustrate the ability of our tools to localize conformational changes, shedding light of commonalities of structures which would otherwise appear as radically different.Our tools are available within the Structural Bioinformatics Library (http://sbl.inria.fr). We anticipate that they will be of interest to perform structural comparisons at large, and for remote homology detection.