Allosteric Activation through Coordinated Energy Landscape Reweighting and Information Flow

Area of Science:

• Molecular Biology
• Immunology
• Structural Biology

Background:

• Allosteric activation is often simplified as discrete state transitions, insufficient for explaining dynamic signal transmission in proteins.
• The innate immune adaptor Stimulator of interferon genes (STING) undergoes conformational changes upon ligand binding, but the mechanism of signal propagation remains unclear.

Purpose of the Study:

• To investigate STING activation beyond a simple binary switch model.
• To understand how ligand binding reshapes the conformational ensemble and communication network in STING.

Main Methods:

• Integration of pathway-level conformational change representations with unbiased molecular dynamics simulations.
• Data-driven inference of protein interaction networks.
• Analysis of STING's response to cyclic dinucleotide (C-di-GMP) binding.

Main Results:

• Cyclic dinucleotide binding reweights the conformational energy landscape, suppressing expanded states and stabilizing intermediate conformations.
• Ligand binding reorganizes long-range allosteric communication, condensing pathways and enhancing transmission efficiency.
• STING activation involves ligand-induced reorganization of interaction architecture and focused information flow.

Conclusions:

• STING activation is better described as a dynamic process involving conformational ensemble reweighting and communication network reorganization, rather than a discrete structural switch.
• Ligand binding dynamically modulates STING's allosteric communication pathways, optimizing signal transmission for innate immune responses.