Abstract
Proteins such as enzymes perform their function by predominant
non-covalent bond interactions between transiently interacting units.
There is an impact on the overall structural topology of the protein,
albeit transient nature of such interactions, that enable proteins to
deactivate or activate. This aspect of the alteration of the structural
topology is studied by employing protein structural networks, which are
node-edge representative models of protein structure, reported as a
robust tool for capturing interactions between residues. Several methods
have been optimised to collect meaningful, functionally relevant
information by studying alteration of structural networks. In this
article, different methods of comparing protein structural networks are
employed, along with spectral decomposition of graphs to study the
subtle impact of protein-protein interactions. A detailed analysis of
the structural network of interacting partners is performed across a
dataset of around 900 pairs of bound complexes and corresponding unbound
protein structures. The variation in network parameters at, around and
far away from the interface are analysed. Finally, we present
interesting case studies, where an allosteric mechanism of structural
impact is understood from communication-path detection methods. The
results of this analysis are beneficial in understanding protein
stability, for future engineering and docking studies.
Keywords: Protein structural networks, graph spectral analysis,
protein-protein interaction, transient association, allostery, network
alterations1. Introduction
The importance of molecular flexibility for a protein to function is
well documented. The analysis of different structural states helps in
analysing its function. Several proteins are very rigid and exist in
fewer distinct conformations. However, most proteins exist predominantly
in an inactive state and seldom in an active state. The difference
between the structural states arises from subtle changes in local
conformations at specific sites or from large structural excursions with
altered topology. Some proteins also populate an intermediate state
which may be stabilised in a dynamic equilibrium due to strong
interactions. The stabilisation of such a transient state is generally
brought about by external perturbations like post translational
modifications, mutations, or various binding partners. One such scenario
is the perturbation of the protein structure due to binding with another
protein. The changes brought about at the site of their interface is
generally allosterically transmitted across the structure of the protein
to impact or present its active site. Although this is intuitive to
understand, the mechanism of this signalling has not been thoroughly
analysed across all proteins.
The analysis of allosteric signalling can often be approached using
protein structural networks (PSN). It is a simplistic mathematical model
of the residue interactions that exist in a well-ordered globular
protein structure, where the residues are considered as nodes and any
interaction between them is considered by drawing an edge between them.
The edge signifies a relationship between the interacting residues,
generally pertaining to features such as non-covalent bonding, proximity
between atoms in space and sometimes also based on energy parameters
that can be defined for interactions.
A further advancement on the use of these structure networks is the
application of a graph-spectral method for the global comparison of
proteins. This method is robust and sensitive to even minute structural
perturbations that can be observed between any pair of networks that are
given as input. The method described by Vasundhara and co-workers is an
advanced comparison metric that has been applied in the validation of
protein structure models and in understanding the amount of structural
variability in an ensemble of structures of a given protein. The method
has been employed in the current work for the global comparison of PSNs.
We have compared the bound and the unbound forms of the same protein,
that has been crystallised when bound to interacting partners as well as
independently. The ProPairs database is a large consortium of available
bound and unbound proteins structures and provides this information. Any
changes in network parameters, both local and global, are discussed
along with interesting clinically relevant scenarios where the network
may have changed considerably without affecting its overall structure
topology. The rearrangement, gain and loss of network connectivity are
discussed further, illustrated using case studies.