Molecular Dynamics Studies of Lipophilic Small Molecule TRPV1 Ligands in Lipid Bilayers

Abstract

Many lipophilic small molecule ligands (drugs and natural compounds) are known to interact with ion channels, but often experimental approaches to address these interactions prove costly and time-consuming. Studies of these ligands using molecular dynamics (MD) simulations in an explicit lipid bilayer system can aid our understanding of their possible mechanisms of action with the target ion channels. Capsaicin, the active ingredient of chilli, and related vanilloid ligands specifically modify the activity of the TRPV1 ion channel and are thought to interact with the transmembrane (TM) region of the channel protein. However, many details of this interaction such as the orientation of capsaicin and the involvement of other domains of the channel remain unknown. In this study we employ MD simulations to define the interactions of capsaicin and its analogues with lipid bilayers. Our simulations have shown that capsaicin spontaneously partitions into phospholipid bilayers and preferentially localizes at the bilayer/water interface. They also suggest the possibility of capsaicin flip-flop from one side of the bilayer to the other. These and related results are discussed in the context of understanding the significance of the lipid bilayer environment to the orientation and kinetics of the interaction of vanilloid ligands with TRPV1.