Stability and dynamics of cyclic diguanylic acid in solution

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Cyclic diguanylic acid (CDG) is a crucial bacterial second messenger.
• CDG regulates essential processes like motility, biofilm formation, and virulence.
• The aggregation state and solution behavior of CDG remain poorly understood.

Purpose of the Study:

• To characterize the dynamics and stability of metal-free and Mg(2+)-bound CDG.
• To elucidate the binding mechanisms of CDG within protein environments.
• To provide fundamental insights into bacterial signaling networks mediated by CDG.

Main Methods:

• Atomistic molecular dynamics simulations.
• Free energy calculations.
• Analysis of CDG conformations and metal ion coordination.

Main Results:

• The CDG dimer is thermodynamically favored over two individual CDG molecules in solution.
• The Mg(2+) ion in the crystal structure dissociates from the CDG dimer in solution, preferring water coordination.
• CDG can adopt both U-shaped and quasilinear monomer conformations when bound to proteins, with minimal energy differences.

Conclusions:

• The slight energetic preference for the CDG dimer suggests it may not bind to proteins via sequential monomer addition.
• The facile conformational adaptation of CDG monomers facilitates binding to diverse protein targets.
• These findings advance our understanding of CDG's role in bacterial physiology and signaling.