Local Bilayer Hydrophobicity Modulates Membrane Protein Stability

Through the insertion of nonpolar side chains into the bilayer, the hydrophobic effect has long been accepted as a driving force for membrane protein folding. However, how the changing chemical composition of the bilayer affects the magnitude of the side-chain transfer free energies (Delta G(sc)(0)) has historically not been well understood. A particularly challenging region for experimental interrogation is the bilayer interfacial region that is characterized by a steep polarity gradient. In this study, we have determined the Delta G(sc)(0) for nonpolar side chains as a function of bilayer position using a combination of experiment and simulation. We discovered an empirical correlation between the surface area of the nonpolar side chain, the transfer free energies, and the local water concentration in the membrane that allows for Delta G(sc)(0) to be accurately estimated at any location in the bilayer. Using these water-to-bilayer Delta G(sc)(0) values, we calculated the interface-to-bilayer transfer free energy (Delta G(i,b)(0)). We find that the Delta G(i,b)(0) are similar to the biological, translocon-based transfer free energies, indicating that the translocon energetically mimics the bilayer interface. Together these findings can be applied to increase the accuracy of computational workflows used to identify and design membrane proteins as well as bring greater insight into our understanding of how disease-causing mutations affect membrane protein folding and function.

Automated summary

This study determined an empirical correlation between the surface area of nonpolar side chains, transfer free energies, and local water concentration in the membrane, allowing for accurate estimation of Delta G(sc)(0) at any location in the bilayer. Additionally, the calculated interface-to-bilayer transfer free energy values were found to be similar to biological translocon-based transfer free energies, suggesting that the translocon mimics the bilayer interface energetically.