The lipid bilayer strengthens the cooperative network of membrane proteins.

Membrane proteins fold and function in a lipid bilayer constituting cell membranes. Nonetheless, their structure and function can be recapitulated in diverse amphiphilic assemblies whose compositions deviate from native membranes. It remains unclear how various hydrophobic environments stabilize membrane proteins and whether lipids play any unique role in protein stability compared to other types of amphiphiles. Here, using the evolutionarily unrelated α-helical and β-barrel membrane proteins from Escherichia coli, we find that the hydrophobic thickness and the strength of amphiphile-amphiphile packing in amphiphilic assemblies are critical determinants of protein stability. Lipid solvation enhances protein stability by facilitating residue burial in the protein interior, reminiscent of the lipophobic effect. This lipid-mediated mechanism also strengthens the cooperative residue-interaction network, promoting the propagation of local structural perturbations throughout the protein. This study demonstrates the pivotal role of lipid solvation in modulating the stability of membrane proteins and their responses to external stimuli.