Fig. 1: Design strategies for binding conformational flexible IDPs or IDRs.
From: Diffusing protein binders to intrinsically disordered proteins
A, Design approach. Aa, Disordered structures of the selected targets. Left, AF2 structure predictions for VP48, BRCA1, ARATH and FUS, coloured by pLDDT scores25, and NMR structures of amylin (PDB ID: 2KB8) and CP (PDB ID: 1T0C). Targeted regions are shown as spheres. Right, diffusion models for proteins are trained to recover noised protein structures and to generate new structures by reversing the corruption process through iterative denoising of initially random noise into a realistic structure. Five representative trajectories are shown for amylin, which result in five different conformations of the target. Ab, Diffusion with constrained secondary structure. Left, AF2 predictions for G3BP1 and IL-2RG25. Right, a modified version of RFdiffusion was trained, allowing for specification of the secondary structure of a region to be helix or strand conformations, along with the sequence. B, Two-sided partial diffusion. Varying the extent of initial noising (top row) enables control over the extent of the introduced structural variation (colours indicate new designs, and grey denotes the parent design).
