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pH-Driven β2AR Dynamics Reveal Loop-Mediated Allosteric Communication.

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Constant-pH molecular dynamics revealed that pH changes affect the flexibility of loops in the beta-2 adrenergic receptor (β2AR) by altering protonation states. These shifts influence receptor dynamics without inducing activation-like states.

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Area of Science:

  • Biochemistry
  • Computational Biology
  • Structural Biology

Background:

  • Membrane protein structure and dynamics are sensitive to environmental factors like pH.
  • Changes in pH alter the protonation states of ionizable residues, affecting protein electrostatics and stability.
  • Constant-pH molecular dynamics (CpHMD) allows dynamic proton exchange, simulating pH effects on proteins.

Purpose of the Study:

  • To investigate the influence of pH variations on the local conformational behaviors of the beta-2 adrenergic receptor (β2AR).
  • To explore how dynamic protonation changes affect receptor loop flexibility and communication pathways.

Main Methods:

  • Applied constant-pH molecular dynamics (CpHMD) at pH 6.5, 7.0, and 8.0.
  • Performed conventional molecular dynamics (MD) with fixed protonation states for comparison.
  • Analyzed loop flexibility, hydrogen-bonding patterns, and communication between receptor regions using mutual information analysis.

Main Results:

  • Loop regions rich in titratable residues (ICL3, ECL2) showed the most significant response to pH changes.
  • CpHMD revealed pH-dependent redistribution of loop flexibility and hydrogen-bonding, unlike constrained behavior in fixed-protonation simulations.
  • Key GPCR microswitches remained in inactive states, indicating pH primarily affects local loop dynamics.

Conclusions:

  • pH variations modulate the local dynamics and flexibility of the beta-2 adrenergic receptor (β2AR) through protonation state changes.
  • Altered communication between extracellular and intracellular loops was observed under different pH conditions.
  • Incorporating pH effects in molecular simulations is crucial for understanding GPCR behavior.