Allosteric Activation through Coordinated Energy Landscape Reweighting and Information Flow

Allosteric activation is commonly depicted as a ligand-driven transition between discrete structural states, yet such descriptions fail to explain how regulatory signals are dynamically organized and transmitted across protein architectures. In the innate immune adaptor Stimulator of interferon genes (STING), structural studies have resolved closed and open conformations of the ligand-binding domain, but how ligand binding reshapes the continuous conformational ensemble and its internal communication network remains unclear. Here, we integrate pathway-level representations of conformational change with extensive unbiased molecular dynamics and data-driven inference of interaction networks to examine STING activation beyond a binary structural switch. Binding of the cyclic dinucleotide C-di-GMP selectively reweights the conformational energy landscape, suppressing highly expanded states while stabilizing intermediate activation-prone conformations. Concomitantly, ligand binding reorganizes long-range allosteric communication by condensing dispersed, interface-dependent signal routes into shorter and predominantly intrachain pathways, thereby focusing information flow and enhancing transmission efficiency. Together, these results support a model in which STING activation is not adequately described as a discrete structural switch, but is associated with ligand-induced reorganization of interaction architecture, focusing of internal information flow, and reweighting of conformational energetics and kinetics within a physically accessible ensemble.