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Using simulation to probe membrane defects with a pH‐sensitive peptide

The pH Low Insertion Peptide (pHLIP) binds, folds and inserts spontaneously into the membrane as a transmembrane helix under acidic conditions. This functionality makes pHLIP a promising tool for drug delivery and diagnostic imaging of disorders associated with acidosis, such as arthritis, cancer, and ischemia. The acidic sensitivity of pHLIP arises from the sequential protonation of its acidic residues which, after binding to the membrane, induces simultaneous folding and insertion in order to seclude its hydrophobic segment from aqueous solvent. However, the peptide‐bilayer interactions of pHLIP in the fully inserted state are poorly understood. Our aim is to characterize the effect of deprotonation of the acidic residues of pHLIP on the stability of the peptide and the bilayer in its inserted state. Our hypothesis is that increasing the degree of deprotonation of pHLIP disrupts favorable interactions between pHLIP and the bilayer. In order to test our hypothesis, we carried out molecular dynamics (MD) simulations of α‐helical pHLIP inserted into a 1‐palmitoyl‐2‐oleoyl‐sn‐3‐phosphocholine (POPC) bilayer. Our variable was the protonation state of the acidic residues in pHLIP. Our results show that in the fully protonated state, pHLIP remains stable. Interestingly, in the fully deprotonated state, the negatively‐charged residues remain embedded in the interior of the bilayer, stabilized by a defect that allows for interactions with waters from bulk solvent. In addition, deprotonation of the C‐terminal acidic residues leads to greater destabilization of pHLIP in the bilayer. Together, these results reveal several of the interactions between pHLIP and the aqueous and lipid phases that are critical in maintaining the fully inserted state of the peptide.