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Protein–Ligand Interactions: Thermodynamic Basis and Mechanistic Consequences

  1. Harvey F Fisher

Published Online: 19 MAY 2010

DOI: 10.1002/9780470015902.a0001341.pub2

eLS

eLS

How to Cite

Fisher, H. F. 2010. Protein–Ligand Interactions: Thermodynamic Basis and Mechanistic Consequences. eLS. .

Author Information

  1. University of Kansas School of Medicine, Kansas City, Kansas, USA

Publication History

  1. Published Online: 19 MAY 2010

This is not the most recent version of the article. View current version (16 MAR 2015)

Abstract

It is difficult to imagine any biological process that is not initiated by the binding of some chemical entity (or ‘ligand’) to a protein. Thus, enzymatic catalysis, signal transduction, ion channel activity, immune responses and the various events involved in genetic expression are all obvious examples of events which, at the molecular level, must begin with the binding of some ligand to a specific binding site on a protein molecule. Furthermore, as each one of these processes proceeds along its reaction pathway, modulation of the affinities of such ligands, positive and negative interactions caused by the binding of other ligands and the release of these ligands either in their original or in altered form constitute obligatory steps in the driving forces and controlling restraints that adapt them to their specific tasks. We extend the basic conceptions set forth in this article to a more detailed level focused on the fundamental nature of ligand–ligand interactions of a protein–ligand complex and the energetic mechanistic consequences to which they lead.

Key Concepts:

  • Every biological reaction is initiated by a protein–ligand binding step.

  • Such reactions never involve the binding of only a single ligand or a single step.

  • The binding of two ligands to the same protein always involves a mutual interaction.

  • The product of a ligand-binding reaction is a new entity in itself; its structure and its properties may differ substantially from the simple sum of those of its initial components.

  • The concept of G Weber's ‘thermodynamic square’ permits the evaluation of a variety of interaction parameters.

  • Patterns of interaction parameters provide a basis for exploring ligand-binding energy transduction.

  • Measurement of ligand-binding heat by techniques using higher levels of mathematical integration provide more detailed dissection into parameters such as enthalpy, entropy, heat capacity and their corresponding interaction terms.

  • The ‘fluctuating protein’ concept suggests that protein reactions proceed as multiple traces on multidimensional free-energy landscapes.

  • Consequences of the thermodynamic complexity of ligand binding suggest new views of such processes as enzymatic catalysis, signalling events and evolutionary aspects.

Keywords:

  • proteins;
  • ligands-binding;
  • thermodynamics;
  • cooperativity;
  • free energy;
  • enthalpy;
  • entropy;
  • heat capacity;
  • enzymes