Human ATP binding-cassette (ABC) transporters are one of the largest families of membrane proteins and perform diverse function. Many of them are also involved in multi-drug resistance that often results in cancer patient treatment poor outcome. Here, we present the structural bioinformatics studies of six human ABC membrane transporters with cryo-EM structures (ABCB7, ABCC8, ABCD1, ABCD4, ABCG1, ABCG5) and their AlphaFold2 predicted water-soluble QTY variants. In the native structures, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F) in the transmembrane helices. These hydrophobic amino acids are systematically replaced by hydrophilic amino acids glutamine (Q), threonine (T) and tyrosine (Y). Therefore, these QTY variants become water-soluble. We also present the superimposed structures of native ABC transporters and their water-soluble QTY variants. The superimposed structures show remarkable similarity with RMSDs between 1.064 Å and 3.413Å despite significant changes to the protein sequence of the transmembrane domains (41.90-54.33%). We also show the differences of hydrophobicity patches between the native ABC transporters and their QTY variants. We explain the rationale why the QTY membrane protein variants become water-soluble. Our bioinformatics studies provide insight into the differences between the hydrophobic helices and hydrophilic helices, and will likely further stimulate designs of water-soluble multispan transmembrane proteins and other aggregated proteins.
**PBD files do not have unstructured loops or C- and N-termini removed. **