Example - oxidation of the hERG potassium channel. This figure is an application example of using PyTMs in conjunction with SWISS modeling, introducing multiple modifications and demonstrating the possibility of modeling stereochemical variants. As the structure of hERG is only partially resolved, a complete model of the intracellular C-terminal domain of hERG1 (residues 667-865) was generated as described in the implementation using SWISS modeling. Using PyTMs, this model was then doubly modified by cysteine oxidation and methionine oxidations. Selected residues are displayed as spheres. Methionine oxidation was performed on object copies introducing either the configurational Methionine sulfoxide R-isomer (red oxygen) or the S-isomer (yellow oxygen). Note that these configurational isomers are superimposed to highlight the differential positioning and do not coexist on the same residue. Cysteine oxidation is not racemic (orange oxygen). Oxidation of hERG1, especially at CYS723, has been previously demonstrated to result in an accelerated deactivation of the associated ion channel. A) An overview of a homo-tetramer of hERG1 intracellular C-terminal domains, as viewed from above i.e. from the cell membrane or pore. The equivalent monomers are colored either blue or light gray for better distinction. The viewing positions for C) and D) are indicated. B) This view corresponds to A, but the complex is viewed from the side. Selected residues have been labeled, as indicated. Note the critical cysteine 723 at the dimer interface. C) A close-up view of the critical oxidized CYS723 at the dimer interface viewed from outside the complex (cf. A). Note how the polar oxygen extends the range of the cysteine residue to interfere with the adjacent loop (ASP767 and THR768). Expectedly, a resulting increase in steric displacement can explain the previously reported increase in deactivation rate. D) A close-up view from inside the complex focusing on adjacent Methionine sulfoxide residues.