Carba-NAD binding activates SIR2 by reshaping conformational plasticity and rewiring long-range allosteric networks

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Allosteric regulation allows proteins to transmit signals across distances, but mechanisms are often unclear.
• Yeast SIR2, an NAD⁺-dependent deacetylase, serves as a model to study cofactor-induced conformational changes.

Purpose of the Study:

• To systematically elucidate how cofactor binding alters yeast SIR2's dynamics and internal communication.
• To identify the molecular pathways involved in allosteric signal transmission.
• To explore potential druggable sites for modulating SIR2 activity.

Main Methods:

• Multiple 3-μs molecular dynamics simulations were performed.
• A graph-based deep learning model (Neural Relational Inference) was employed.
• Signal-pathway analysis was conducted to map communication networks.

Main Results:

• A reproducible "core-locking with peripheral-release" dynamic mode was identified upon cofactor binding.
• The β1-α2 loop rigidified, while distal modules became more flexible.
• Newly identified "relay-type" residues (e.g., Pro214, Thr224) were found to mediate the allosteric cascade.
• A druggable distal cavity overlapping with relay residues was discovered.

Conclusions:

• Cofactor binding to SIR2 induces a specific dynamic mode and establishes a novel relay-style allosteric network.
• The identified cavity represents a rational target for developing small-molecule allosteric activators.
• Targeting this cavity could lead to longevity-promoting interventions by modulating NAD⁺-dependent pathways.