Sequence-Similar Protein Domain Pairs With Structural or Topological Dissimilarity.

Abstract

For a variety of applications, protein structures are clustered by sequence similarity, and sequence-redundant structures are disregarded. Sequence-similar chains are likely to have similar structures, but significant structural variation, as measured with RMSD, has been documented for sequence-similar chains and found usually to have a functional explanation. Moving two neighboring stretches of backbone through each other may change the chain topology and alter possible folding paths. The size of this motion is compatible to a variation in a flexible loop. We search and find domains with alternate chain topology in CATH4.2 sequence families relatively independent of sequence identity and of structural similarity as measured by RMSD. Structural, topological, and functional representative sets should therefore keep sequence-similar domains not just with structural variation but also with topological variation. We present BCAlign that finds Alignment and superposition of protein Backbone Curves by optimizing a user chosen convex combination of structural derivation and derivation between the structure-based sequence alignment and an input sequence alignment. Steric and topological obstructions from deforming a curve into an aligned curve are then found by a previously developed algorithm. For highly sequence-similar domains, sequence-based structural alignment better represents the chains motion and generally reveals larger structural and topological variation than structure-based does. Fold-switching protein pairs have been reported to be most frequent between X-ray and NMR structures and estimated to be underrepresented in the PDB as the alternate configuration is harder to resolve. Here we similarly find chain topology most frequently altered between X-ray and NMR structures.