Abstract: Membrane proteins and water-soluble proteins share a similar core. This similarity suggests that it should be possible to water-solubilize membrane proteins by mutating only their lipid-exposed residues. Computational tools and methods are disclosed herein that can be used to design water-soluble variants of helical membrane proteins, using the pentameric phospholamban (PLB) and potassium channel KcsA as models. To water-solublize PLB, the membrane-exposed positions were changed to polar or charged amino acids, while the putative core was left unaltered. We generated water-soluble phospholamban (WSPLB), and compared its properties to its predecessor PLB. As a probe of the correctness of the fold of the water soluble KcsA, the computationally designed proteins contain an agitoxin-2 binding site from a mammalian homologue of the channel. The resulting proteins express in high yield in E.