The human erythrocyte sialoglycoprotein glycophorin A (GpA) has been used extensively in experiment and simulations as a model of transmembrane helix-dimer formation, emphasizing the critical role of specific residue-residue interactions between helices in dimer stability. While the tertiary dimer structure is modulated by the hydrophobic lipid bilayer environment, we show that interactions of GpA with ordered interfacial water are commensurate to intrahelical forces. The role of lipid-water interface in stabilizing transmembrane proteins is not yet understood; however, dramatic water reordering in the presence of the transmembrane domains is observed from simulations and is possibly measurable by experiment. Interfacial interactions including anisotropic interactions with the polar headgroups might favor parallel association of transmembrane helices. To quantify forces capable of disrupting the GpA dimer, we generate folding/unfolding intermediates by replacement of the lipid bilayer with water, eliminating not only the native hydrophobic environment but also the native interfacial water region. Dramatic changes in the secondary, helical structures occur, with a transition from i,i+4 α-helix to i,i+5 π-helix and concomitant perturbation of the tertiary structure. Enforcing the native α-helix secondary structure by soft dihedral restraints restores the native tertiary structure, in essence substituting for the lack of the lipid-water interface. We suggest that differentiation between interactions within the lipid bilayer, including interactions with lipid headgroups and water can enrich our understanding of the thermodynamic stability of transmembrane domains.