It is theoretically possible to avoid misfolding into non-covalent lasso entanglements using small molecule drugs
Fig 3
Simply stabilizing the native entanglement is not an effective way to rescue misfolded DDLB proteins.
(a) The 3D structure of a coarse-grained ligand model. The interaction sites are colored magenta, and the covalent bonds are colored white. The principal axes of the mass distribution tensor are indicated by dashed arrows, with the maximum bond length from the central bead listed. (b) Native DDLB protein structure highlighting the native entanglement in Domain III (green dashed circle) and the predicted ligand binding site (yellow). The CG ligand (magenta) is shown bound to the target site. Entanglements are depicted as in Fig 1. (c) An initial structure of the nascent DDLB protein of 190 residues (cyan) on the ribosome (white) in the presence of the ligand (magenta). (d) Probabilities of natively entangled structure formation at length 230 (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 probability vs. nascent chain (NC) length (top) and the averaged fraction of native contact formed in Domain III vs. NC 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. (g) A structure of the enriched misfolded state P3 with the ligand bound (left) and the non-native entanglement topology diagram (right, loop: 98–116; crossing: 186). Entanglements are depicted as in Fig 1.