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.