Structural investigation of MscL gating using experimental data and coarse grained MD simulations

Area of Science:

• Biophysics
• Structural Biology
• Molecular Mechanosensation

Background:

• Mechanosensitive channel of large conductance (MscL) is a model for mechanosensation.
• Understanding MscL gating and open states is crucial for physiological functions like osmoregulation.
• High-resolution closed-state structures exist, but open-state details remain elusive.

Purpose of the Study:

• To investigate the structural changes during MscL gating.
• To elucidate the mechanism of MscL channel opening.
• To explore the role of membrane tension in MscL function.

Main Methods:

• Combined coarse-grained simulations with Electron Paramagnetic Resonance (EPR) and Förster Resonance Energy Transfer (FRET) experiments.
• Achieved extensive conformational sampling to model MscL gating.
• Generated plausible open-pore structures consistent with existing data.

Main Results:

• Developed plausible open-pore structures for MscL.
• Identified membrane thinning as an inducer of a kink in the TM1 helix.
• Observed outward movement of the periplasmic loop away from the pore center due to the TM1 kink.

Conclusions:

• The study provides insights into MscL gating mechanisms.
• A novel structural change involving a TM1 kink induced by membrane thinning is proposed.
• This finding suggests a new mechanism for tension sensing potentially linked to osmoregulation.