Interaction of tryptophan analogs with POPC lipid bilayers investigated by molecular dynamics calculations

Several experimental structures of integral membrane proteins have demonstrated that tryptophan side chains are found preferentially within the membrane interface, but no clear physical explanation for this preference has been demonstrated. The present work contains a series of molecular dynamics simulations designed to provide insight into this phenomenon. Specifically, we performed conventional unbiased simulations, as well as biased molecular dynamics of indole and N-methylindole within palmitoyloleoyl phosphatidylcholine (POPC) bilayers. The unbiased calculations examined the behavior of the indoles in three environments-the membrane center, the headgroup region, and the water outside the membrane. The biased calculations were performed using a new dynamic windowing procedure, which efficiently moved the indoles through the bilayer. These calculations allowed us to explore the orientation, hydrogen bonding, and energetics of the indole, as a function of its location along the membrane normal. Furthermore, free energy profiles were constructed from the biased simulations, facilitating comparison to experiment and a possible explanation of indole's partitioning behavior.