Comparing local search paths with global search paths on protein residue networks: allosteric communication

TL;DR

This study explores how proteins function as navigable small-world networks, revealing that local search paths are more biologically relevant for intra-protein communication than global paths, especially due to short-range clustering.

Contribution

It demonstrates the biological significance of local search paths in protein networks and identifies key structural features that facilitate intra-protein communication.

Findings

Local search paths avoid long-range, unstable edges.

Short-range edges cluster in energy transport structures.

Disruption of these structures impairs intra-protein communication.

Abstract

Although proteins have been recognized as small-world networks and their small-world network properties of clustering and short paths have been exploited computationally to produce biologically relevant information, they have not been truly explored as such, i.e. as navigable small-world networks in the original spirit of Milgram's work. This research seeks to fill this gap by exploring local search on a network representation of proteins and to probe the source of navigability in proteins. Previously, we confirmed that proteins are navigable small-world networks and observed that local search paths exhibit different characteristics from global search paths. In this paper, we investigate the biological relevance of the differences in path characteristics on a type III receptor tyrosine kinase (KIT). A chief difference that works in favour of local search paths as intra-protein communication pathways is their weaker proclivity, compared to global search paths, for traversing long-range edges. Long-range edges tend to be less stable and their inclusion tends to decrease the communication propensity of a path. The source of protein navigability is traced to clustering provided by short-range edges. The majority of a protein's short-range edges reside within structures deemed important for long-range energy transport and modulation of allosteric communication in proteins. Therefore, the disruption of intra-protein communication as a result of the destruction of these structures via random rewiring is expected. A local search perspective leads us to this expected conclusion while a global search perspective does not. These findings initiate the compilation of a list of path properties that are characteristic of intra-protein pathways and could suggest fresh avenues for evolving and regulating navigable (small-world) networks.