Fig. 6: PreMode in-silico mutagenesis mode-of-action predictions on BRAF.

a PreMode predictions visualized with BRAF protein domains, x-axis are annotations and amino acid changes, y-axis are amino acid positions. The first few columns indicate Alphafold2 pLDDT, relevant solvent accessibility, secondary structures, protein domains, respectively. The left panel showed PreMode’s pathogenicity predictions and labels used in training, pink indicates predicted pathogenic, light blue indicates predicted benign, red indicates pathogenic, and blue indicates benign in training data, white indicates reference amino acid. The right panel showed PreMode’s G/LoF predictions and labels used in training, pink indicates predicted GoF, light blue indicates predicted LoF, white indicates predicted benign. Red indicates GoF and blue indicates LoF in training data. b Folding energy change upon mutations of Braf phorbol-ester/DAG-type zinc finger domain on the inactive state (Braf-14-3-3 binding, y-axis) versus active state (Braf-Kras binding, x-axis), colored by PreMode predictions, a few known cancer driver mutations were labeled. c Folding energy change upon mutations of Braf kinase domain on the inactive state (y-axis) versus active state (x-axis), colored by PreMode predictions, a few known cancer driver mutations were labeled. d. Folding energy change upon mutations of BRAF-MEK1 complex. X-axis showed the ddG on BRAF-MEK1 complex, y-axis showed the ddG on BRAF active conformation alone (left panel, PDB: 4MNE), colored by PreMode predictions.