Date of Original Version
Free-energy landscapes for short peptides—specifically for variants of the pH low insertion peptide (pHLIP)—in the heterogeneous environment of a lipid bilayer or cell membrane are constructed, taking into account a set of dominant interactions and the conformational preferences of the peptide backbone. Our methodology interprets broken internal H-bonds along the backbone of a polypeptide as statistically interacting quasiparticles, activated from the helix reference state. The favored conformation depends on the local environment (ranging from polar to nonpolar), specifically on the availability of external H-bonds (with H2O molecules or lipid headgroups) to replace internal H-bonds. The dominant side-chain contribution is accounted for by residue-specific transfer free energies between polar and nonpolar environments. The free-energy landscape is sensitive to the level of pH in the aqueous environment surrounding the membrane. For high pH, we identify pathways of descending free energy that suggest a coexistence of membrane-adsorbed peptides with peptides in solution. A drop in pH raises the degree of protonation of negatively charged residues and thus increases the hydrophobicity of peptide segments near the C terminus. For low pH, we identify insertion pathways between the membrane-adsorbed state and a stable trans-membrane state with the C terminus having crossed the membrane.
Physical Review E
Sharma, G. P., Meyer, A. C., Habeeb, S., Karbach, M., & Müller, G. (2022). Free-energy landscapes and insertion pathways for peptides in membrane environment. Phys. Rev. E, 106, 014404. https://doi.org/10.1103/PhysRevE.106.014404
Available at: https://doi.org/10.1103/PhysRevE.106.014404