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bioRxiv · 10.1101/483081

Hydrodynamic and electrophoretic properties of Trastuzumab/HER2 complexes. Experiments and modeling.

Ramos, J.·Vega, J. F.·Cruz, V.·Sanchez-Sanchez, E.·Cortes, J.·Martinez-Salazar, J.
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Abstract

The combination of hydrodynamic and electrophoretic experiments and computer simulations is indeed a powerful approach to study the interaction between proteins. In this work, we present hydrodynamic and electrophoretic experiments in aqueous solution along with molecular dynamics and hydrodynamic modeling to monitor and compute biophysical properties of the interactions between the extracellular domain of the HER2 protein (eHER2) and the monoclonal antibody trastuzumab (TZM). The importance of this system relies on the fact that the overexpression of HER2 protein is related with the poor prognosis breast cancers (HER2++ positives) being the TZM a monoclonal antibody for the treatment of this cancer. We have found and characterize two different complexes between the TZM and eHER2 proteins (1:1 and 1:2 TZM:eHER2 complexes). The conformational features of these complexes regulate their hydrodynamic and electrostatic properties. Thus, the results indicate a high degree of molecular flexibility in the systems, that ultimately leads to higher values of the intrinsic viscosity and as well as lower values of diffusion coefficient than those expected for simple globular proteins. A highly asymmetric charge distribution is detected for the monovalent complex (1:1 complex), which has strong implications in correlations between the experimental electrophoretic mobility and the modeled net charge. In order to understand the dynamics of these systems and the role of the specific domains involved, it is essential to find biophysical correlations between dynamics, macroscopic transport and electrostatic properties. The results should be of general interest for researchers working in this area.

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Ramos, J., Vega, J. F., Cruz, V., Sanchez-Sanchez, E., Cortes, J., Martinez-Salazar, J.. 2018-12-04. Hydrodynamic and electrophoretic properties of Trastuzumab/HER2 complexes. Experiments and modeling.. https://doi.org/10.1101/483081

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