Last week at our group meeting I presented on a paper titled “T-cell Receptor Variable beta Domains Rigidify During Affinity Maturation” by Monica L. Fernández-Quintero, Clarissa A. Seidler and Klaus R. Liedl. The authors use metadynamics simulations of the same T-cell Receptor (TCR) at different stages of affinity maturation to study the conformational landscape of the complementarity-determining regions (CDRs), and how this might relate to an increase in affinity. Not only do they conclude that affinity maturation leads to rigidification of CDRs in solution, but they also present some evidence for the conformational selection model of biomolecular binding events in TCR-antigen interactions.

Along with the induced fit model, the conformational selection model is one of two popular models describing the nature of biomolecular interactions. The former states that in solution, a protein adopts a low-affinity conformation. Upon productive collision with its binding partner, a weak binding event occurs, followed by conformational rearrangement that results in the protein adopting a new, high-affinity state. The conformational selection model, on the other hand, argues that the high-affinity conformation of a protein is already being sampled whilst in solution and that productive binding is likely to occur when a copy of the protein that is already in the appropriate binding pose collides with its binding partner.

The authors begin by showing that even in static crystal structures of TCRs, we find an increased number of stabilising interactions within the CDRs, suggesting rigidification. By using a metadynamics approach, they then go on to demonstrate that the conformational landscape of higher-affinity TCRs is markedly different to those with lower affinity. Most strikingly, Fernández-Quintero et al conclude that there is a decrease in the number of sampled conformers in solution. Lastly, the authors show through simulations of the TCR in its bound and unbound forms that conformations sampled by the bound form are part of the solution-state ensemble, providing support for the conformational selection mode of binding. It is always interesting to gain insight into the dynamics of protein structures, and there is something satisfying about results that so clearly support a particular model!