pH (Low) Insertion Peptides (pHLIPs) are a unique family of membrane peptides that undergo conformational changes in response to a pH stimulus; in particular, they spontaneously fold and insert into lipid membranes at acidic pH, whereas they are otherwise disordered at the membrane surface.<br/>Early pHLIP research has resulted in a preliminary picture of pHLIP’s secondary structure and position in the membrane; however, common experimental methods such as FTIR, fluorescence, X-ray crystallography, and mass spectrometry cannot access the dynamical information required to deduce a mechanism for folding and insertion.<br/>This research overcomes these limitations with a combined spectroscopic (linear and multidimensional infrared) and computational (molecular dynamics) approach. Infrared (IR) experiments have been used to assess specific information about the secondary structure in different environments, and all-atom molecular dynamics (MD) have been used to explore the same ensembles on an atomistic level. By applying electrostatic frequency maps to classical MD trajectories, structural hypotheses can be tested against spectroscopic data to inform experimental interpretation on a previously inaccessible atomistic level. With these tools, a preliminary structural model of pHLIP’s insertion depth and angle has been developed.<br/>The introduction of isotope labels brings an additional set of structural constraints by offering site-specific information both experimentally and computationally. By inducing a spectral frequency shift, strategically placed isotope labels can elucidate pHLIP secondary structure, dynamics, and membrane interaction at the residue level, allowing for identification of key residues involved in the folding and insertion process.<br/>Furthermore, two-dimensional IR spectroscopy (2D IR) has begun to reveal spectral diffusion and electrostatic interactions between the pHLIP backbone and the lipid head groups at different solution pH. Comparison of low- and high- pH systems gives preliminary insight into the mechanism of insertion and folding as well as pHLIP structure and behavior at the lipid-water interface.

Computational and spectroscopic studies of pH (Low) insertion peptides in lipid membranes

255th National Meeting (2018)

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