Computational engineering of water-soluble human potassium ion channels through QTY transformation.

Transmembrane potassium ion channels are crucial for ion transport, metabolism, and signaling, and serve as promising targets for anti-cancer therapies. However, their hydrophobic transmembrane nature requires detergents, posing a major bottleneck for experimental handling. In this paper, we present a structural bioinformatics study of six experimentally determined and twelve modeled potassium channel structures, in which hydrophobic amino acids (L, I/V, and F) were systematically replaced with neutral hydrophilic ones (Q, T, and Y), making the proteins more water-soluble. QTY (computationally predicted) and native (experimental and repredicted) variants show remarkable structural similarity (RMSD: ~0.50 Å - ~2.14 Å) despite significant sequence differences. QTY variants, both rigid and refined with MD simulations, maintain comparable to native variants stability, solvent-accessible surface area (SASA), and ionic, aromatic, and van der Waals interactions but differ in the grand average of hydropathy (GRAVY), solubility, and hydrophobic contacts. Overall, our study presents a computational approach for designing hydrophilic potassium ion channels while maintaining the native global structure that could potentially simplify their practical use by eliminating the need for detergents.
Competing Interests: Declarations Competing interests Massachusetts Institute of Technology (MIT) has filed several patent applications for the QTY code for GPCRs, and OH2Laboratories has obtained a license from MIT to develop water-soluble GPCR variants. However, this article does not focus on GPCRs. One of the authors, S.Z., is an inventor of the QTY code and holds a minor equity position in OH2Laboratories. S.Z. has also founded a startup called 511 Therapeutics, which aims to develop therapeutic monoclonal antibodies targeting solute carrier transporters for the treatment of pancreatic cancer. S.Z. holds a majority equity position in 511 Therapeutics. PT Metiska Farma partially sponsored the study but had no influence or interference in the study design, data collection, analysis, interpretation of data, manuscript writing, or decision to publish the results. All other authors declare no competing interests. Ethical approval It is a purely digital structural biology study utilizing publicly accessible in silico programs. We state that: i) all methods were conducted in compliance with applicable guidelines and regulations; ii) all experimental protocols received approval from an institutional and licensing committee; and iii) no human biological samples or human subjects were involved in this study.
(© 2024. The Author(s).)