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Binding interactions of fatty acyl lipid mediators within the vanilloid pocket of TRPV1: A molecular dynamics study published in Elsevier Prostaglandins & Other Lipid Mediators

Our research paper titled Binding interactions of fatty acyl lipid mediators within the vanilloid pocket of TRPV1: A molecular dynamics study, authored by Nada Birkic, David Visentin, Željko Svedružić, and Christian A. Reynolds has been published in Volume 169 of Elsevier journal Prostaglandins & Other Lipid Mediators.

Highlights

  • TRPV1 can be activated by various endovanilloid lipid mediator ligands.
  • Molecular dynamic simulations reveal lipid mediator -TRPV1 binding interactions.
  • Lipid mediators with similar structures bind similarly within the vanilloid pocket.
  • Polar groups within the ligands’ acyl tails directly impact binding stability.

Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel is a ligand-gated, nonselective cation channel expressed in primary sensory neurons, which has a role in nociception. The channel is activated by noxious heat, pH, capsaicin and other endogenous vanilloids, including lipid mediators (LMs) enzymatically derived from polyunsaturated fatty acids (PUFA). Although capsaicin binding to TRPV1 has been well characterized, the molecular mechanism by which endogenous LM ligands bind the channel is not well understood. In this study, we characterized the binding interactions for 13 endogenous LM ligands, within the vanilloid pocket of TRPV1 using a molecular dynamics (MD) approach. We observed that LM ligands can be grouped based on their structure and affinity for the vanilloid pocket. Furthermore, the position as well as the number of the polar groups on the LM ligand directly impact binding stability through various polar interactions with the protein. As an additional control we performed docking experiments of the PUFA precursor molecules linoleic acid and arachidonic acid which failed to form stable interactions within the vanilloid pocket. While LM ligands with similar structures displayed similar binding interactions, there were notable exceptions in the case of 20-HETE, 9-HODE, and 9,10-DiHOME. Our study offers new insights into the mechanisms involved in TRPV1 activation by endogenous LM ligands. The observed binding interactions may assist in the interpretation of in vivo and in vitro pharmacodynamics studies.

Read the full paper in Elsevier Prostaglandins & Other Lipid Mediators Volume 169.