1. Introduction
The existence and functioning of any organism can be seen to be solely due to proteins in its cellular environment. Most of the functionalities arise due to several interactions of proteins with various macromolecular entities like nucleic acids, lipids, carbohydrates, etc., or with other proteins. Among these interactions, protein-protein interactions (PPIs) are of primary importance as these interacting complexes play crucial roles in several cellular processes like replication, transcription, translation, regulation, signaling, etc.. These protein-protein complexes (PPCs) can be categorized into different groups based on the proportion of interacting protomers or stability of protomers or the lifetime of interactions into homo/hetero complexes or obligate/non-obligate complexes or permanent/transient complexes, respectively. The complexes where the protomers become unstable when they are separated are obligates, while the complexes where the interactors remain stable even though they are separated are non-obligates. On the other hand, the complexes where the protomers interact throughout their functional lifetime are permanent, while the complexes where the protomers associate and dissociate temporarily are transient complexes. In general, obligate complexes are permanent both structurally and functionally, while non-obligate complexes are mostly transient associations with a few permanent associations like antibody-antigen complexes. One of the great examples of such interaction could be the heterotrimeric G protein. G protein consists of three subunits: α, β, and γ, where β and γ subunits interact throughout their lifetime, making it a permanent interaction. Instead, the α subunit interacts transiently to βγ complex when inactive and dissociates when active, making it a transient interaction. Among these, transient interactions are of utmost importance as these complexes are crucial for various biological processes as they act as hubs in protein-protein interaction networks (PPINs), are multi-specific, are great drug targets and are involved in various cellular processes.
There are several studies that distinguish structural characteristics of such interaction types amongst proteins and PPIs. Few such physicochemical properties which discriminate permanent and transient interactions are contact area, interface shape and size, number of contacts, polarity, hydrophobicity, complementarity of the interface, involvement of secondary structures at the interface, evolution of the interface, etc. Based on these properties, several groups focused on distinguishing these two types of PPIs. Few groups focused solely on the physicochemical properties or interfacial properties to predict permanent and transient PPIs. Some groups represented these physicochemical properties into vectors for better prediction using machine learning approaches, while some researchers used desolvation energy explicitly to predict permanent and transient. Apart from these, some used sequence features to predict permanent or transient and few developed algorithms which do not require information about binding partners for prediction.
After the first enzyme was solved, it was found that there are some distinct lobes present within the protein. However, the term ‘domain’ was coined by Wetlaufer by defining these entities as structurally independent regions within proteins. These domains are also referred to as units of protein evolution. Several structure-based identification and analysis of domains have been performed and organized as databases. The vast functional diversity of a protein arises by combining such domains into a single polypeptide chain, calling it a multi-domain protein, and most proteins, even in a simple proteome, are multi-domain proteins. The interactions amongst multi-domain proteins with other such proteins are mainly carried out by a portion of the protein structure, a protein domain, rather than the whole protein. The interactions between domains are called domain-domain interactions (DDIs), and they generally facilitate protein interactions. It is also observed that interacting domain pairs tend to co-evolve with each other in an interaction in order to maintain a better interaction. The domain pairs are also consistent with their parent protein interactions. There are few studies that take help of known structural DDIs to predict PPIs, whether these are input sequences or structures. Deng and coworkers used maximum likelihood approach to estimate the probabilities of domain pairs in protein interactions to predict PPIs. A J Gonzalez and Li Liao used fisher scores derived from the domain interaction profiles as features to predict DDI using SVM, which can be used to predict PPI. Instead of using generative methods of predicting PPI, Zhao et al. used information of both PPI and non-PPI to infer DDI, which in turn can be used again to predict PPI from the inferred DDIs. Similarly, Sprinzak and Margalit used correlated sequence signatures in proteins to predict DDI.
Often, functional characteristics of a multi-domain protein is dependent on the arrangement of the domains in it and interactions among them, which can be compared to arrangement of words to form meaningful sentences in natural languages. Interactions among the domains facilitate proper functioning of multi-domain proteins. These domains are also known to be responsible for functional and evolutionary relationship of proteins. The occurrence of multiple domains also confers additional stability to individual domains and hence the whole protein. Hence, there is a need to study inter-domain interactions, mostly in monomeric proteins, for their resident time of interactions or strength of interactions which could provide immense knowledge about the functional and structural aspects of multi-domain proteins. However, unlike studies differentiating PPIs into permanent and transient interactions, there is no systematic and organized approach to classify DDIs into permanent and transient interactions. Instead, there are a few studies which investigate DDIs in a single polypeptide chain and regard such interactions to be either permanent interactions or to have characteristics intermediate between PPIs.
In this work, we extended the concept of permanent and transient interactions to intra-protein inter-domain interactions and characterized the underlying interaction types. Using a dataset of monomeric two domain proteins whose domain definitions are taken from SCOPe, we could identify such domain interactions to be either permanent or transient. Permanent and transiently interacting domains are not much different in terms of evolution of the interface, and the type of functions they are involved in, when investigated human proteome only. However, we found that these two types of DDI differ in their physicochemical properties of their interface, dynamically correlated motion of their residues, and preference for choosing its interacting partner. This work would shed light on the principles of domain interactions, prediction of domain orientation, and protein functioning by these rules of domain interactions. Structurally, this study would also help to understand the folding of multi-domain proteins correctly in the near future.