Mechanisms of Multi-Step Protein-Ligand Interactions

Proteins function through their interactions with other molecules. In some cases, the binding is simple and may be explained by a single step reaction between the free and bound states. Often, however, the process is much more complex involving intermediate states and the formation of higher order complexes, which may lead to very complicated responses to the ligand binding. Much of our understanding and way of thinking about multivalent protein interactions in the form of allostery and cooperativity come from the seminal work of Monod, Wyman, Changeux and Perutz on hemoglobin and the alternative interpretation by Koshland, Némethy and Filmer. Another important example of multivalent ligand interactions is the binding of antibodies to antigens and the concept of avidity addressing the thermodynamic consequences of several binding sites.

In recent years our understanding of the complexity of protein-ligand interactions has been challenged by the mechanisms by which several intrinsically disordered proteins bind their ligands. Some of the most striking examples are complexes that remain completely disordered and complexes where one ligand can replace another ligand at equal concentration even though the two ligands appear to have the same dissociation constants in the absence of the other ligand. Advances in the characterization of conformational changes and transient structures have provided a detailed understanding of the molecular mechanisms underlying how the catalytic activity of monomeric enzymes may be regulated cooperatively by the substrate. Advanced kinetic modelling of ligand binding has also demonstrated spurious kinetic effects in complex formation that may be of key importance for the regulation of cellular processes. Finally, the giant leap in DNA sequencing techniques now allows analysis of huge ligand libraries that can provide insight about sequence determinants for the ligand binding process that could only be dreamt about a decade ago.

In this Research Topic we wish to collect a series of research reports and reviews that demonstrate how multi-step protein ligand binding reactions can by characterized and how protein function can by fine-tuned through exchange between multiple states. The contributions will focus on both experimental and theoretical aspects of the molecular mechanisms of the binding reactions. Topics of interest include, but are not limited to:

• Binding kinetics
• Binding thermodynamics
• Binding models / kinetic modelling
• Conformational change
• Experimental methods for characterizing multi-step binding
• Ligand binding intermediates
• Biochemical regulation