Journal of Molecular Modeling

, Volume 19, Issue 3, pp 1227–1236

Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis

  • Juan Felipe Franco-Gonzalez
  • Victor L. Cruz
  • Javier Ramos
  • Javier Martínez-Salazar
Original Paper

DOI: 10.1007/s00894-012-1661-3

Cite this article as:
Franco-Gonzalez, J.F., Cruz, V.L., Ramos, J. et al. J Mol Model (2013) 19: 1227. doi:10.1007/s00894-012-1661-3


Human epidermal growth factor receptor 2 (ErbB2) is a transmembrane oncoprotein that is over expressed in breast cancer. A successful therapeutic treatment is a monoclonal antibody called trastuzumab which interacts with the ErbB2 extracellular domain (ErbB2-ECD). A better understanding of the detailed structure of the receptor-antibody interaction is indeed of prime interest for the design of more effective anticancer therapies. In order to discuss the flexibility of the complex ErbB2-ECD/trastuzumab, we present, in this study, a multi-nanosecond molecular dynamics simulation (MD) together with an analysis of fluctuations, through a principal component analysis (PCA) of this system. Previous to this step and in order to validate the simulations, we have performed a detailed analysis of the variable antibody domain interactions with the extracellular domain IV of ErbB2. This structure has been statically elucidated by x-ray studies. Indeed, the simulation results are in excellent agreement with the available experimental information during the full trajectory. The PCA shows eigenvector fluctuations resulting in a hinge motion in which domain II and CH domains approach each other. This move is likely stabilized by the formation of H-bonds and salt bridge interactions between residues of the dimerization arm in the domain II and trastuzumab residues located in the CH domain. Finally, we discuss the flexibility of the MD/PCA model in relation with the static x-ray structure. A movement of the antibody toward the dimerization domain of the ErbB2 receptor is reported for the first time. This finding could have important consequences on the biological action of the monoclonal antibody.

Trastuzumab Fab approaching the ErbB2 dimerization arm


Extracellular ErbB2 receptorHerceptinMolecular dynamicsPrincipal component analysisTrastuzumab

Supplementary material

894_2012_1661_MOESM2_ESM.pdf (221 kb)
The file “MM-PBSA_calculation.pdf” contains details about the binding energy calculation. (PDF 221 kb)
894_2012_1661_MOESM1_ESM.pdf (1.3 mb)
The file “Additional_information.pdf” contains the following information: Fig. S1. Secondary structures along the trajectory of the different domains found in the ErbB2-ECB/trastuzumab-fab complex as calculated by DSSP analysis. Fig. S2.a) Root mean square deviations (RMSD) as a function of simulation time of the ErbB2-ECD receptor backbone atoms in the complex. b) RMSD along the MD simulation for the backbone atoms for each of the individual domains defined in the ErbB2-ECD protein (domain I in black, II in red, III in green and IV in blue). The complex ErbB2-ECD/trastuzumab-fab crystal structure (PDB code: 1N8Z) was used in all cases as reference structure. (PDF 1322 kb)
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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Juan Felipe Franco-Gonzalez
    • 1
  • Victor L. Cruz
    • 1
  • Javier Ramos
    • 1
  • Javier Martínez-Salazar
    • 1
  1. 1.BIOPHYM, Macromolecular Physics DepartmentInstituto de Estructura de la Materia, CSICMadridSpain