Protein–Protein Interactions: The Structural Foundation of Life Complexity


The amazing variety of protein functions are often covered by protein complexes, so understanding protein–protein interactions means coming deeply into the functional role of proteins in life.

In the last years, the investigation of protein–protein interactions has become central in many fields, spanning from molecular biology to pharmacology. In this article, we present a state of the art of methods for such investigation, along with perspectives of applications. We stressed the multiscale nature of approaches, longing from genome‐wide analysis to the detailed study of protein–protein interface on single residues.

The most innovative approaches, based on complex network theory, shed a very bright light on future trends for protein–protein applications on drug design and on molecular therapy for diseases where protein association plays a pivotal role (misfolding).

Key Concepts

  • Protein–protein interactions underlie several physiological mechanisms.
  • The analysis of protein–protein interfaces is crucial to quantify protein complex stability.
  • Hotspot residues provide the largest contribution to protein–protein binding energy.
  • Experimental methods point to identify hotspots and quantify binding energy.
  • Molecular docking allows a fine analysis of protein–protein interface.
  • Network‐based approaches clarify the multiscale nature of protein–protein interactions.

Keywords: protein–protein interactions; hotspots; protein–protein interface; computational methods; network pharmacology; drug design

Figure 1. Protein backbone fractal dimension.Reproduced with permission from Di Paola et al. © American Chemical Society.
Figure 2. A conceptual map of PPI prediction methods.Reproduced with permission from Keskin et al. © American Chemical Society.
Figure 3. The five categories of computational PPI methods: (a) genome based; (b) evolutionary relationship; (c) protein docking (surface complementarity); (d) domain similarities; (e) sequence based.Reproduced with permission from Pitre et al. © Springer.
Figure 4. Types of protein–protein interface in homodimers.Reproduced with permission from Mei et al. © John Wiley & Sons Ltd.
Figure 5. Haemoglobin clustering partition; (a) protein contact network is represented by the adjacency matrix (dots in the matrix plot correspond to contacts between residues – network edges); (b) modules identified by spectral clustering are in different colours on the ribbon structure representation; (c) the clustering colour map reports a projection of cluster partition onto sequences (nodes – residues – are reported on both axes): zones of the same colours represent clusters, blue is the background colour; (d) the P–z diagram sketches connectivity in terms of the Guimerà–Amaral.Reproduced with permission from L. Di Paola and A. Giuliani © Elsevier.
Figure 6. Network pharmacology paradigm. Reproduced with permission from Csermely et al. © Elsevier.


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Further Readings

Dömling A , Mannhold R , Kubinyi H and Folkers G (2013) Protein‐Protein Interactions in Drug Discovery. John Wiley & Sons.

Janin J (2002) Protein Modules and Protein‐Protein Interactions. Elsevier Science.

Mangani S (2013) Disruption of Protein‐Protein Interfaces: In Search of New Inhibitors. Berlin Heidelberg: Springer.

Scott DE , Bayly AR , Abell C and Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein‐protein interaction challenge. Nature Reviews Drug Discovery 15 (8): 533–550.

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Paola, Luisa Di, and Giuliani, Alessandro(May 2017) Protein–Protein Interactions: The Structural Foundation of Life Complexity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001346.pub2]