Ultrafast vibrational dynamics of the tyrosine ring mode and its application to enkephalin insertion into phospholipid membranes as probed by two-dimensional infrared spectroscopy.

Enkephalins are small opioid peptides whose binding conformations are catalyzed by phospholipid membranes. Binding to opioid receptors is determined by the orientation of tyrosine and phenylalanine side chains. In this work, we investigate the effects of different charged phospholipid headgroups on the insertion of the tyrosine side chain into a lipid bilayer using a combination of 2D IR spectroscopy, anharmonic DFT calculations, and third order response function modeling. The insertion is probed by using the ∼1515 cm-1 tyrosine ring breathing mode, which we found exhibits rich vibrational dynamics on the picosecond timescale. These dynamics include rapid intramolecular vibrational energy redistribution (IVR), where some of the energy ends up in a dark state that shows up as an anharmonically shifted combination band. The waiting-time dependent 2D IR spectra also show an unusual line shape distortion that affects the extraction of the frequency-frequency correlation function (FFCF), which is the dynamic observable of interest that reflects the tyrosine side chain's insertion into the lipid bilayer. We proposed three models to account for this distortion: a hot-state exchange model, a local environment dependent IVR model, and a coherence transfer model. A qualitative analysis of these models suggests that the local environment dependent IVR rate best explains the line shape distortion, while the coherence transfer model best reproduced the effects on the FFCF. Even with these complex dynamics, we found that the tyrosine ring mode's FFCF is qualitatively correlated with the degree of insertion expected from the different phospholipid headgroups.