It is theoretically possible to avoid misfolding into non-covalent lasso entanglements using small molecule drugs
Fig 6
Ligand destabilizing native closed loop rescues misfolded CAT-III.
(a) Predicted non-native structure of CAT-III N-terminal region. The structure is colored from red to blue from N-terminal tail to C-terminal tail. The predicted ligand binding site is shown in yellow, with the CG ligand presented inside. (b) Starting structure used in the binding affinity scan. (c) One of the starting structures of the RNC complex with a CG ligand present used in the co-translational folding simulations. (d) Probabilities of native state formation (PNative, blue) and ligand binding (PBinding, orange) vs. the interaction energy εij (see Method). Error bars represent the 95% confidence intervals (CIs) estimated by bootstrapping. (e) Ligand binding probabilities vs. nascent chain length in the co-translational phase (left) and vs. time in the post-translational phase (right). Representative structures are presented on the top to depict the ligand binding. (e) Ligand binding probabilities vs. nascent chain length in the co-translational phase (top left) and vs. time in the post-translational phase (top right), and the averaged fraction of native contact formed between segments I and III (〈Q1|3〉) vs. post-translation time with (red) and without (blue) ligand present (bottom). Transparent stripes represent 95% CIs estimated by bootstrapping. (f) Probabilities of forming the misfolded entangled state P13 (red) and native state P14 (blue) vs. post-translational time for the fast CAT-III variant with (right) and without (left) ligand present. Transparent stripes represent 95% CIs estimated by bootstrapping.