Temperature sensitive contact modes allosterically gate TRPV3.

Area of Science:

• Biophysics
• Molecular Biology
• Computational Biology

Background:

• TRPV ion channels are crucial molecular sensors for temperature.
• While cryo-EM structures offer insights into channel states, the precise mechanisms of temperature sensing remain unclear.
• Understanding these mechanisms is vital for comprehending thermal sensation and related physiological processes.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying temperature sensitivity in TRPV3 channels.
• To identify specific residue-residue interactions and networks that mediate allosteric temperature sensing.
• To demonstrate the predictive power of these interactions on channel gating dynamics.

Main Methods:

• Molecular dynamics simulations
• Multi-ensemble contact analysis
• Graph theory and network analysis
• Machine learning (random forest model)

Main Results:

• Identified temperature-sensitive residue clusters with distinct contact frequency profiles.
• Revealed temperature-dependent changes in channel community structure and identified a high-centrality contact network regulating gating.
• Demonstrated that the contact states of specific temperature-sensitive modes predict the channel gate's state.
• Validated findings by identifying functionally critical residues reported in existing literature.

Conclusions:

• The study reveals specific residue-level temperature response patterns driving TRPV3 channel dynamics.
• A network of critical contacts facilitates allosteric regulation of channel gating by temperature.
• These findings provide high-resolution insights into thermo-TRP channel function and highlight the utility of temperature-sensitive contact analysis.