Large-scale state-dependent membrane remodeling by a transporter protein

Area of Science:

• Structural biology
• Membrane biophysics
• Computational biochemistry

Background:

• Membrane proteins, including channels and transporters, can alter cell membrane shape.
• The energetic cost of these membrane deformations is often overlooked but crucial for protein function.
• The Na+-aspartate symporter GltPh exhibits drastic structural changes during its transport cycle.

Purpose of the Study:

• To investigate the membrane deformations induced by the Na+-aspartate symporter GltPh.
• To quantify the free-energy cost associated with these protein-induced membrane shape changes.
• To understand the role of membrane deformations in the functional mechanism of transporters.

Main Methods:

• Utilized molecular simulations to model the interactions between GltPh and the lipid bilayer.
• Employed a novel simulation methodology to estimate the free-energy cost of membrane deformations.
• Analyzed the structural changes of GltPh protomers transitioning to an inward-facing conformation.

Main Results:

• Inward-facing GltPh protomers induce deep, long-ranged, and independent membrane deformations.
• The estimated free-energy cost for this membrane perturbation is approximately 6-7 kcal/mol per protomer.
• These results suggest that membrane deformations are a significant energetic factor in transporter function.

Conclusions:

• Membrane deformations are substantial and energetically costly for transporters like GltPh.
• Stabilizing forces, either internal or environmental, must compensate for this energy cost to enable function.
• The findings provide new insights into the mechanism of neurotransmitter transporters and related proteins.