A study on structural conservation of intra chain domain domain interfaces

Abstract

A protein domain is considered as a modular conserved region of protein sequence or compact region of tertiary structure that serves as an evolutionary/functional unit of protein. Domains combine to form multidomain protein, which can facilitate complex biological functions. Analyses of many genomes have shown that only a limited repertoire of domain combinations is observed in genomes. The structural analyses of multidomain proteins have been largely focused on characterizing domain orientation. However, most of these have not analyzed domain-domain interfaces or explored their structural relatedness. In thesis work, we have comprehensively and systematically investigated the conservation of intra-chain domain interfaces in multidomain proteins from closely to distantly or completely unrelated domains. This study can facilitate accurate modeling of interfaces in multidomain proteins. In order to characterize intra-chain domain interfaces (DDI), we first compared various approaches to define domain interfaces. Thus, defined domain interfaces were compared with protein-protein interaction interfaces (PPIs) in terms of physicochemical features, amino acid propensity and secondary structure content. The study showed that domain-domain interface size is relatively smaller than protein interfaces. Despite this, interfaces of domains and proteins are similar in almost all analyzed features such as hydrophobicity, average number of hydrogen bonds and secondary structures. We examined the extent of domain interface conservation in multiple structures of a multidomain protein. This showed that in general domain interfaces are conserved (average interfacial rmsd ~1.3Å) for most proteins. The variation in domain interface is found due to interaction with ligand/DNA/RNA. Further, we compared domain interface conservation among domains sharing a level of structural relatedness as defined in structural domain database CATH. The interface similarity as assessed by IS-score, showed closely related domains conserve interfaces wit