"Membrane Hydrophobicity Gradients as it Relates to Membrane Protein Stability in Computational Studies"
Membrane hydrophobicity has long been considered the driving force in protein stability for membrane proteins inside the lipid bilayer. Insertion of the protein into the membrane itself is also believed to be dependent on the hydrophobicity gradient of the water-to-bilayer transition. Understanding of how the hydrophobic gradient within the lipid bilayer effects individual residues throughout a transmembrane protein is limited and has been difficult to observe. Recent studies have investigated the variation of hydrophobicity within the lipid bilayer as it relates to the individual hydrophobicity of amino acid residues inside the transmembrane regions of the protein.(1) Both computational and experimental methods on OmpLA protein, used as the model protein, resulted in novel energy calculations used to determine the side-chain transfer free energy ΔGosc as well as the interface-to-bilayer transfer free energy ΔGoi,b.1 Similar research methods also using OmpLA protein have investigated membrane protein insertion energies (2) compared to values from the Moon and Fleming hydrophobicity scale.(3) This information is extremely important for both design of membrane protein computational simulations that are accurate and correctly mimic natural life as well as for the creation of artificial membrane proteins relevant for biological processes.(4)
(1) Marx, D. C.; Fleming, K. G. Local Bilayer Hydrophobicity Modulates Membrane Protein Stability. J. Am. Chem. Soc. 2021, 143 (2), 764–772.
(2) Alford, R. F.; Fleming, P. J.; Fleming, K. G.; Gray, J. J. Protein Structure Prediction and Design in a Biologically Realistic Implicit Membrane. Biophysical Journal 2020, 118 (8), 2042–2055.
(3) Moon, C. P.; Fleming, K. G. Side-Chain Hydrophobicity Scale Derived from Transmembrane Protein Folding into Lipid Bilayers. Proc Natl Acad Sci USA 2011, 108 (25), 10174.
(4) Ulmschneider, J. P.; Smith, J. C.; White, S. H.; Ulmschneider, M. B. The Importance of the Membrane Interface as the Reference State for Membrane Protein Stability. Biochimica et Biophysica Acta (BBA) - Biomembranes 2018, 1860 (12), 2539–2548.