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Frameworks for understanding long-range intra-protein communication - PubMed

Review

Frameworks for understanding long-range intra-protein communication

Matthew J Whitley et al. Curr Protein Pept Sci. 2009 Apr.

Abstract

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.

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Figures

Fig. 1
Fig. 1

A schematic summary of the two basic frameworks for understanding long-range intra-protein communication. (a) The sequential (KNF) model whereby a series of small conformational changes resulting from induced fit ligand binding propagates to a distal site in the protein, changing its conformation and making the binding of a second ligand more favorable. (b) The conformational ensemble viewpoint developed from the MWC model of ligand binding. The high and low affinity states are populated at all times, though to differing degrees. Ligand binding by the high affinity state, although relatively rare on account of its smaller population, stabilizes that state and redistributes the populations in the conformational ensemble, leading to the eventual dominance of the high affinity state.

Fig. 2
Fig. 2

A representation of the conformational ensemble framework for long-range communication. Perturbing the system can lead to two possible outcomes. (a) Perturbation shifts the original population distribution (gray curve) to a new distribution having a global energetic minimum at a new average conformation (black curve). (b) The ensemble is perturbed such that the global minimum (and thus the average conformation) of the original distribution (gray curve) does not change; rather, the width of the distribution becomes either wider (dotted curve) or narrower (black curve), representing a respective gain or loss of conformational entropy.

Fig. 3
Fig. 3

A stereoscopic view of the consequences of peptide binding to PDZ2 from human tyrosine phosphatase 1E (adapted from PDB code 1D5G). The bound peptide (black) perturbs the ps-ns dynamics of methyl-bearing side chains distal to the binding site. The perturbed distal side chains are shown as gray van der Waals surfaces. For clarity, perturbed side chains that directly interact with the peptide are not shown.

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