Title:An Analysis of Central Residues Between Ligand-Bound and Ligand-Free Protein Structures Based on Network Approach
Volume: 24
Issue: 6
Author(s): Arumugam Amala and Isacc Arnold Emerson *
Affiliation:
- School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu,India
Keywords:
Holo and apo proteins, residue centrality, center of mass, shortest path length, clustering coefficient, conservation
score, mutational analysis.
Abstract: Background: Depiction of protein structures as networks of interacting residues has
enabled us to understand the structure and function of the protein. Previous investigations on closeness
centrality have identified protein functional sites from three- dimensional structures. It is well
recognized that ligand binding to a receptor protein induces a wide range of structural changes.
Objective: An interesting question is how central residues function during conformational changes
triggered during ligand binding? The aim of this study is to comprehend at what extent central residues
change during ligand binding to receptor proteins.
Method: To determine this, we examined 37 pairs of protein structures consisting of ligand-bound
and ligand-free forms. These protein structures were modelled as an undirected network and significant
central residues were obtained using residue centrality measures. In addition to these, the
basic network parameters were also analysed.
Results: On analysing the residue centrality measures, we observed that 60% of central residues
were common in both the ligand-bound and ligand-free states. The geometry of the central residues
revealed that they were situated closer to the protein center of the mass. Finally, we demonstrated
the effectiveness of central residues in amino acids substitutions and in the evolution itself. The
closeness centrality was also analyzed among different protein domain sizes and the values gradually
declined from single-domains to multi-domain proteins suggesting that the network has potential
for hierarchical organization. Betweenness centrality measure was also used to determine the central
residues and 31% of these residues were common between the holo/apo states.
Conclusion: Findings reveal that central residues play a significant role in determining the functional
properties of proteins. These results have implications in predicting binding/active site residues,
specifically in the context of drug designing, if additional information concerning ligand
binding is exploited.
