The cost of living in the membrane: A case study of hydrophobic mismatch for the multi-segment protein LeuT

► Membrane deformation cannot alleviate completely the hydrophobic mismatch in multi-TM proteins. ► A non-conserved membrane-facing residue K288 in LeuT causes large membrane deformation. ► Water penetration and membrane bending near K288 affects neighboring hydrophobic residues. ► The cost of mismatch at TM1a impedes its outward movement required for function. ► Effect of residual hydrophobic mismatch at TM1a is eliminated in the K288A mutant and transport efficiency is increased.