Abstract
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.