Fig. 6: Computational and experimental evaluation of our designed C-terminal peptide extensions.

a Workflow of our C-terminal extension design process. b MM/GBSA energy distributions for top peptides generated by the four VAE-MH models. c MM/GBSA energies of top ten peptides for each of the two C-terminal extensions. Error bars represent standard deviations. d Crystal structures of TCF-bound β-catenin (PDBid: 1G3J, 2GL7, and 3OUW). e Sequence alignment of selected peptide extensions (with MM/GBSA-binding energy below −40 kcal/mol) for YPEDILDKHLQRV-based extension (4–9 residues). f Sequence alignment of selected peptide extensions (with MM/GBSA-binding energy below −40 kcal/mol) for YPEDILDKHLQRVIL-based extension (2–7 residues). g Initial and final structures along with their superimposition of the best peptide CAL-2 bound to β-catenin during the MD simulation. Extension residues and β-catenin residues crucial for binding are labeled and represented in stick. Sample sizes in (b) for YPEDILDKHLQRVIL-based extension and YPEDILDKHLQRV-based extension are n = 45 and n = 54, respectively. In the left panel of (b), boxes bound the interquartile range of (Q1 = −45.3, median = −41.5, Q3 = −37.8) for Pretrain, (Q1 = −43.8, median = −40.8, Q3 = −39.2) for Fine-tune1, (Q1 = −44.6, median = −43.6, Q3 = −44.6) for Fine-tune2, and (Q1 = −46.5, median = −45.4, Q3 = −43.2) for Fine-tune3; whiskers represent the most extreme values of (minima = −45.3, maxima = −37.8) for Pretrain, (minima = −47.1, maxima = −37.2) for Fine-tune1, (minima = −49.1, maxima = −39.4) for Fine-tune2, and (minima = −49.2, maxima = −39.9) for Fine-tune3. In the right panel of (b), boxes bound the interquartile range of (Q1=-47.0, median = −44.2, Q3 = −42.9) for Pretrain, (Q1 = −45.4, median=-41.4, Q3 = −39.1) for Fine-tune1, (Q1 = −48.6, median=-44.3, Q3 = −42.5) for Fine-tune2, and (Q1 = −49.8, median = −45.8, Q3 = −43.7) for Fine-tune3; whiskers represent the most extreme values of (minima = −50.2, maxima = −33.2) for Pretrain, (minima = −54.4, maxima = −34.7) for Fine-tune1, (minima = −55.3, maxima = −35.5) for Fine-tune2, and (minima = −53.3, maxima = −37.9) for Fine-tune3. In (c), whiskers indicate standard deviations for triplet measurements. Source data are provided as a Source Data file.