Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis
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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.
KeywordsExtracellular ErbB2 receptor Herceptin Molecular dynamics Principal component analysis Trastuzumab
Thanks are due to the, Comision Interministerial de Ciencia y Tecnologia (CICYT) (MAT2009-12364 and MAT2012-36341 projects) for financial support. The authors also acknowledge Secretaria General Adjunta de Informatica- Consejo Superior de Investigaciones Cientificas (SGAI-CSIC) for technical support during the simulations. One of us (J.R) thanks for financial support through the Ramon y Cajal program, contract RYC-2011-09585. Very fruitful conversations with Dr. Rafael Nuñez during the discussion of literature experimental details are gratefully appreciated.
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