The transient receptor potential vanilloid-1 (TRPV1) is a tetrameric nonselective cation channel that acts as a conduit for a variety of external stimuli, including noxious heat, acidosis, and ligand binding, whose signaling ultimately leads to pain sensation. Activation gates the channel, allowing the influx of cations, which subsequently depolarizes the neuron. As an alternative to traditional pain treatments, modulating the behavior of TRPV1 is now the focus of significant drug-discovery efforts. Recently cryo-EM structures of TRPV1 in both the closed(apo) and open states have been reported. Such structures provide an exceptional starting point for structure-based drug discovery, as well as, the unraveling of the biophysical features of temperature activation. Using the crystal structure of the intracellular ankyrin unit and these cryo-EM structures, we have recently built a full length model of the apo-human TRPV1 homo-tetramer. The cryo-EM structure of apo-TRPV1 includes density identified with phospholipid both in the vanilloid binding site and an adjacent region between the S1-S2 helices. The role of these phospholipids in the dynamics and activation of TRPV1 remains elusive. In particular PI(4,5)P2 (phosphatidylinositol 4,5 biphosphate), a known ion channel regulator localized on the inner leaflet of plasma membranes, has been implicated in modulating TRPV1. This work has identified C-terminal binding site residues. To obtain an atomic description of the behavior of the TRPV1 channel with bound phospholipid, we have initiated molecular dynamics simulations in a membrane model (POPC). Simulations include the 1) full apo-TRPV1, 2) channel with a phospholipid bound in the S1-S2 site of each monomer, and 3) inclusion of PI(4,5)P2 in the inner leaflet. These simulations are run at physiological as well as elevated temperatures. The results of these simulations will be presented and discussed with respect to experiment and earlier MD studies. [Support:NIDA-RO1-DA003934 to PHR]