Structure and function studies of membrane proteins, particularly G protein-coupled receptors (GPCRs) and multipass transmembrane proteins, require detergents after removing them from cell membranes. We have invented a simple tool, the QTY code, that is named for three amino acids: glutamine (Q), threonine (T), and tyrosine (Y) for making water-insoluble domains become water-soluble without detergents. Despite substantial transmembrane domain changes, the detergent-free QTY variants maintain stable structures and ligand-binding activities. We believe the QTY code will be useful for designing water-soluble variants of membrane proteins and other water-insoluble aggregated proteins. The QTY code designed detergent-free chemokine receptors may be useful in many applications. The QTY variants may not only be useful as reagents in deorphanization studies, but also for designing biologic drugs to treat cancer, autoimmune, or infectious diseases. The QTY code allows membrane proteins to be systematically designed through simple, specific amino acid substitutions. The QTY code is robust and straightforward: it is the simplest tool to carry out membrane protein design without sophisticated computer algorithms. Thus, it can be used broadly. The QTY code has implications for designing additional GPCRs and other membrane proteins, or for rendering water-insoluble and aggregated proteins to become water soluble.