Computational Analysis of Structural and Conformational Dynamics of the HER2 L755S/T862A Double Mutation

Abstract

Background: Mutations that occur either by activation or acquired means in the HER2 kinase domain lead to aberrant signaling of the receptor and response in cancers caused by HER2. Double mutation in L755S/T862A is a condition that has been clinically reported, and this condition causes changes in HER2 signaling and resistance to treatment. However, the effects of such mutations are not well characterized at the molecular level.
Methods: In the current study, molecular dynamics (MD) simulations were used to explore the conformational properties of the HER2 L755S/T862A double mutants as well as the WT protein. The WT protein was subjected to a 200 ns MD simulation run, while two separate 200 ns trajectories were run for the L755S/T862A double mutants. Conformations of the systems were analyzed using the RMSD, RMSF, Rg, and SASA analysis methods.
Results: In comparison with the WT, the mutant L755S/T862A showed an increase in backbone confirmation deviations from the WT, with an increase in RMSD in the latter part of the simulation period. An increase in residue level flexibility was seen for the mutant at certain parts of the protein. Higher values of Rg and SASA were seen for the mutant, reflecting a change in global compactness of the protein in addition to more solvent accessibility compared with the WT.
Conclusion: The current computational analysis elucidates the molecular structural details related to the HER2 L755S/T862A double mutation in terms of conformational changes and serves as an example for investigating this clinical mutation of HER2 protein.