3.1 Intra-protein domain interactions can be further classified as permanent and transient
Interactions between domains in multi-domain proteins are now possible to study with the availability of larger such entries in structural databanks. Moreover, structures are more conserved than sequences, which makes protein studies more accessible. In order to avoid complications of higher order domain interactions, we have considered only interactions arising from two structural domains within a single polypeptide chain which would eliminate the interfering effect of another domain in other chain(s). For this study, we created a protein structural dataset of monomeric two-domain proteins (Figure 1).
Next, the dataset was classified into DDIs which permanently or transiently interact. As the domain interface and subunit interface are somewhat similar, we searched for a tool to predict PPIs as permanent and transient, which could be used for domain interactions within proteins. We chose NOXclass since this is one of the highly accurate classifiers and is easy to use.
From a dataset of 417 monomeric two-domain proteins, only 264 proteins could be classified due to stringent cutoff, and the rest of the proteins were of lower confidence. We observed that around 109 proteins retain permanent inter-domain interactions, while around 154 of them showed to have transient interactions (Figure 2A, Supplementary Table S1) at a stringent cutoff. Comparatively large number of proteins showed to have transient interactions, which could prove their inherent flexibility to accommodate any function of the protein.
There are few studies which compare inter-chain protein interactions to intra-chain interactions and comment on their resident time of interaction. In one such study, the authors analyzed protein interaction sites by taking 750 transient PPIs and 2000 domain interactions within a chain. The authors assumed such domain interactions within the same protein chain as obligate interactions. In another such study, the authors analyzed six different types of interfaces in protein structures, and domain-domain interface within a single chain was one of the six interface types. They viewed such interaction as permanent interaction between independent folding units and compared these with hetero-obligomers. On the other hand, it is also seen that most of the domain interfacial properties within a chain are intermediate between inter-chain permanent and non-obligate complexes. The observations from our study clearly suggest that intra-chain DDIs can also be classified as permanent and transient interactions. Moreover, we could further diverge domain interfaces which are intermediate between permanent and transient PPI into permanent and transient domain interactions, which are discussed in detail in the following sections.