Fig. 1: Structural and mechanistic insights into hotspot HER2 dimerization domain mutations (DDMs).

A Schematic representing the analysis pipeline of The Cancer Genome Atlas BC cohorts to identify the hotspot HER2 DDMs. B Kaplan–Meier curves comparing the overall survival between patients with wild-type HER2 (H2-WT) breast cancer (BC) (unaltered group, n = 2936) and those with HER2 DDMs (altered group, n = 57) demonstrated a hazard ratio of 0.04803 (95% confidence interval (CI): 0.01193–0.1934). C 3D protein structure model of HER2 in open form showing location of the five identified hotspot mutations. D Frequency distribution plot representing root mean square deviation (RMSD) frequency distribution of the monomer structures during 1 μs molecular dynamic simulation (MDS). E Frequency distribution plot of radius of gyration showing stable conformation for H2-WT and S305C, and unstable conformation for G309A, S310Y, and P523S. F, G Charts comparing root mean square fluctuations during MDS between H2-WT and domain II mutations (F); H2-WT and domain IV mutation (G). H Diagonal cross-correlation matrix analysis showing correlated (blue) and anti-correlated (pink) movements during simulation. I RMSD frequency distribution plot of respective homodimer structures during 500 ns MDS. J Line graph representing solvent accessible surface area estimated during simulation for H2-WT and DDMs. K Graph showing solvation gain on complex formation. Dashed trendlines indicate the trend of ΔG values of H2-WT and its DDMs during simulation.