Título:
|
Hydrodynamic and Electrophoretic Properties of Trastuzumab/HER2 Extracellular Domain Complexes as Revealed by Experimental Techniques and Computational Simulations
|
Autor/a:
|
Ramos, Javier; Vega, Juan Francisco; Cruz, Victor; Sanchez-Sanchez, Eduardo; Cortés Castan, Javier; Martinez-Salazar, Javier
|
Otros autores:
|
Institut Català de la Salut; [Ramos J, Vega JF, Cruz V, Sanchez-Sanchez E, Martinez-Salazar J] BIOPHYM, Department of Macromolecular Physics, Instituto de Estructura de la Materia, IEM-CSIC, Madrid, Spain. [Cortes J] Ramón y Cajal University Hospital, Madrid, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Hospital Universitari Vall d'Hebron |
Abstract:
|
Complexos Trastuzumab / HER2; Propietats hidrodinàmiques; Dinàmica molecular |
Abstract:
|
Complejos de trastuzumab / HER2; Propiedades hidrodinámicas; Dinámica molecular |
Abstract:
|
Trastuzumab / HER2 complexes; Hydrodynamic properties; Molecular dynamics |
Abstract:
|
The combination of hydrodynamic and electrophoretic experiments and computer simulations is a powerful approach to study the interaction between proteins. In this work, we present hydrodynamic and electrophoretic experiments in an 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), while the TZM is a monoclonal antibody for the treatment of this cancer. We have found and characterized 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, 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. |
Abstract:
|
This research work was funded by the Spanish Ministry of Economy and Competitiveness (MINECO, Spain) (Project MAT2012-36341-FEDER) and by the CSIC (Spain). J. Ramos acknowledges financial supportthrough the Ramón y Cajal Program (MINECO, Spain)—Contract RYC-2011-09585. |
Materia(s):
|
-Dinàmica molecular -Càncer - Simulació per ordinador -Hidrodinàmica -ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Models, Theoretical::Models, Molecular::Molecular Docking Simulation -PHENOMENA AND PROCESSES::Physical Phenomena::Hydrodynamics -CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal::Antibodies, Monoclonal, Humanized::Trastuzumab -TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::modelos teóricos::modelos moleculares::simulación de acoplamiento molecular -FENÓMENOS Y PROCESOS::fenómenos físicos::hidrodinámica -COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales::anticuerpos monoclonales humanizados::trastuzumab |
Derechos:
|
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
|
Tipo de documento:
|
Artículo Artículo - Versión publicada |
Editor:
|
MDPI
|
Compartir:
|
|