Frameworks for Understanding Long-Range Intra-Protein Communication

The phenomenon of intra-protein communication is fundamental to such processes as allostery and signaling, yet comparatively little is understood about its physical origins despite notable progress in recent years. This review introduces contemporary but distinct frameworks for understanding intra-protein communication by presenting both the ideas behind them and a discussion of their successes and shortcomings. The first framework holds that intra-protein communication is accomplished by the sequential mechanical linkage of residues spanning a gap between distal sites. According to the second framework, proteins are best viewed as ensembles of distinct structural microstates, the dynamical and thermodynamic properties of which contribute to the experimentally observable macroscale properties. Nuclear magnetic resonance (NMR) spectroscopy is a powerful method for studying intra-protein communication, and the insights into both frameworks it provides are presented through a discussion of numerous examples from the literature. Distinct from mechanical and thermodynamic considerations of intra-protein communication are recently applied graph and network theoretic analyses. These computational methods reduce complex three dimensional protein architectures to simple maps comprised of nodes (residues) connected by edges (inter-residue "interactions"). Analysis of these graphs yields a characterization of the protein's topology and network characteristics. These methods have shown proteins to be "small world" networks with moderately high local residue connectivities existing concurrently with a small but significant number of long range connectivities. However, experimental studies of the tantalizing idea that these putative long range interaction pathways facilitate one or several macroscopic protein characteristics are unfortunately lacking at present. This review concludes by comparing and contrasting the presented frameworks and methodologies for studying intra-protein communication and suggests a manner in which they can be brought to bear simultaneously to further enhance our understanding of this important fundamental phenomenon.