The Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel with the greatest permeability to Ca<sup>2+</sup>. Activation of TRPV1 leads to nociceptive pain and is implicated in a number of physiological roles, such as body temperature regulation, inflammation, increase in the blood brain barrier’s permeability, etc. TRPV1 is activated by multiple stimuli, including low pH, noxious heat, and the binding of certain lipids and vanilloid molecules, among which is the exogenous agonist capsaicin.<br/>Interestingly, using a combination of computational and experimental approaches, we recently showed that phosphoinositide lipids, including phosphatidylinositol (PtdIns) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], regulate TRPV1 via functionally distinct binding sites (Yazici A et al., 2021).  <br/>Here we implement a large virtual screening campaign to evaluate the binding preferences for several classes of lipids against each of these allosteric sites. Additionally, to gain further insights into the role of lipids in the process of gating, we perform molecular dynamics simulations of TRPV1, in complex with either agonist or antagonist ligands, to confirm that annular lipids are permanently bound to and stabilize the open state, as suggested experimentally (Gao et al., 2014). Results obtained from our investigations can be used as the basis for characterizing the role of biologically relevant lipids in TRPV1 activation, and as a starting point for the design of new TRPV1 modulators.

Investigating the binding of lipids to TRPV1 channels and their role in gating via computation

ACS Spring 2022

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