On the binding affinity of macromolecular interactions: daring to ask why proteins interact

Abstract

Interactions between proteins are orchestrated in a precise and time-dependent manner, underlying cellular function. The binding affinity, defined as the strength of these interactions, is translated into physico-chemical terms in the dissociation constant (Kd), the latter being an experimental measure that determines whether an interaction will be formed in solution or not. Predicting binding affinity from structural models has been a matter of active research for more than 40 years because of its fundamental role in drug development. However, all available approaches are incapable of predicting the binding affinity of protein–protein complexes from coordinates alone. Here, we examine both theoretical and experimental limitations that complicate the derivation of structure–affinity relationships. Most work so far has concentrated on binary interactions. Systems of increased complexity are far from being understood. The main physico-chemical measure that relates to binding affinity is the buried surface area, but it does not hold for flexible complexes. For the latter, there must be a significant entropic contribution that will have to be approximated in the future. We foresee that any theoretical modelling of these interactions will have to follow an integrative approach considering the biology, chemistry and physics that underlie protein–protein recognition.

Potential of mean force analysis of the self-association of leucine-rich transmembrane α-helices: Difference between atomistic and coarse-grained simulations

“…With the development of new technologies, it is becoming increasingly important to predict protein-protein binding affinities accurately, 40 and therefore, it is necessary to improve CG parameters. In general, it is not difficult to perform force matching on the MARTINI platform; for example, Seo et al 41 performed reparameterization, enabling analysis of changes in the peptide secondary structure by applying the Boltzmann inversion to conformers sampled by the replica exchange method.…”

Energetics of albumin-disuccinylmaslinic acid binding determined by fluorescence spectroscopy

“…A solvent reorganization at the protein surface, upon drug-protein complex formation, is generally considered to be the most significant contributor to DC p [35]. In particular, negative DC p values indicate that the protein surface is removed from contact with solvent when it is associated with the drug to form a complex [36,37]. Inspection of the values of DC p reveals that as the NaCl concentration increases the exposure of protein hydrophobic patches to water decreases, suggesting a loss of solvating water structure in the association process.…”

Techniques for the analysis of protein-protein interactions in vivo

“…The K d describes the concentration of protein A at which it is bound to half of all available sites on protein B at equilibrium (Kastritis and Bonvin, 2013). In other words, the smaller the K d (femtomolar or picomolar range) of a protein pair AB, the higher the affinity of A to B, as fewer molecules of A are needed for 50% of all A molecules to bind to B (Perkins et al, 2010).…”