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TRPV1 is a thermo-sensitive ion channel involved in neurosensory and other physiological functions. The trans-membrane helices of TRPV1 undergo quick and complex conformational changes governed by thermodynamic parameters and membrane components leading to channel opening. However, the molecular mechanisms underlying such events are poorly understood. Here we analysed the molecular evolution of TRPV1 at the lipid-water-interface region (LWI), typically defined as a layer of 6 Å thickness on each side of the membrane with less availability of free water. Amino acids demarcating the end of the trans-membrane helices are highly conserved. Residues present in the inner leaflet are more conserved and have been preferentially selected over others. Amino acids with snorkeling properties (Arginine and Tyrosine) undergo specific selection during the vertebrate evolution in a cholesterol-dependent and/or body temperature manner. Results suggest that H-bond formation between the OH- group of cholesterol and side chain of Arg557 or Arg575 at the inner leaflet is a critical parameter that can regulate channel functions. Different LWI mutants of TRPV1 have altered membrane localization and deficient colocalization with lipid raft markers. These findings may help to understand the lipid-protein interactions, and molecular basis of different neuronal functions. Such findings may have broad importance in the context of differential sensory responses, pathophysiologies, and application of pharmacological drugs such as anaesthetics acting on TRPVs.

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Preferential selection of Arginine at the lipid-water-interface of TRPV1 during vertebrate evolution correlates with its snorkeling behaviour and cholesterol interaction