Temperature sensitive contact modes allosterically gate TRPV3

TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel’s functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate’s state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis.Author summary: Rapid and accurate temperature sensation is critical for organismal survival and homeostasis. In metazoans, members of the TRP ion channel family mediate neurological thermo-sensing. Despite abundant structural details on these channels provided by Cryo-EM, parts of the TRP channel that sense temperature and mechanistic details of channel gating remains an open question. Here we use a novel computational approach for dissecting the residue-level temperature responses of a noxious temperature reporter TRPV3 and offer a high-resolution model for TRPV3 function that accounts for numerous experimental observations.