It is theoretically possible to avoid misfolding into non-covalent lasso entanglements using small molecule drugs
Fig 5
Ligand destabilizing native closed loop rescues misfolded DDLB.
(a) Predicted non-native structure of DDLB segment 126 to 174. 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) Probabilities of natively entangled structure formation at the end of translation (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. (c) Ligand binding probability vs. nascent chain length (top) and the averaged fraction of native contact formed in Domain III vs. nascent chain length with (red) and without (blue) ligand present (bottom). Transparent stripes represent 95% CIs estimated by bootstrapping. (f) Probabilities of forming misfolded entangled states P3 (orange), P4 (red), P8 (magenta), and native state P10 (blue) as a function of post-translational time for the slow DDLB variant with (right) and without (left) ligand present. Transparent stripes represent 95% CIs estimated by bootstrapping.