entropy driven allostery

Our approach is centered on 'Entropy-driven allostery,' a concept originally introduced by Cooper and Dryden. In their seminal 1984 paper, they suggested that the propagation of allosteric signals could be driven entirely by the redistribution of thermal fluctuations within the protein molecule. We understand now that this 'conformational' entropy is closely associated with fast sub-nanosecond thermal motions. As protein atoms oscillate around their equilibrium positions, they don't act in isolation; instead, their interactions can lead to synchronized movements. This synchronization, a well-established phenomenon in physics, is recognized as the self-organization of coupled oscillators. We propose that these transient, dynamically synchronized areas within proteins are the underlying mechanism of entropy-driven allostery as it was suggested by Cooper and Dryden.

The following figure illustrates this idea:

The darker regions represent low-entropy zones within the protein where atoms exhibit high synchronization, moving cohesively as a semi-rigid body. Upon ligand binding at the allosteric site (shown on the right), new connections emerge, increasing synchronization in the vicinity, as shown by the expanded dark area. This shift causes atoms that were once part of the active site's low-entropy cluster to 'change their allegiance,' leading to decreased synchronization and increased entropy around the active site. Consequently, this can significantly alter the active site's binding properties, all without any structural changes.

For the first time, such redistribution of entropy has been experimentally observed using NMR in the Catabolite Activator Protein (CAP) of E.coli by Popovich et al. in 2006. In our latest study, we have applied LSP alignment to analyze the thermal dynamics of this system, successfully demonstrating that our method can track similar redistribution of entropy.

In this figure, entropy in CAP is approximated by Degree Centrality (DC) in the Protein Residue Networks generated by the LSP-alignment tool. Changes in entropy are shown with colors: blue for areas of decreased entropy, and red for areas of increased entropy. When cAMP binds to the left domain, it significantly stabilizes this region, as seen in blue, while the right domain becomes less stable, shown in red. This demonstrates the capability of the method to clearly visualize entropic changes and offer simple, interpretable explanation for entropy-driven allostery, as described by Cooper and Dryden.