Hydrodynamic and Electrophoretic Properties of Trastuzumab/HER2 Extracellular Domain Complexes as Revealed by Experimental Techniques and Computational Simulations
| Autor: | Eduardo Sanchez-Sanchez, Juan Francisco Vega, Javier Martínez-Salazar, Javier Ramos, Javier Cortes, Víctor L. Cruz |
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| Přispěvatelé: | Consejo Superior de Investigaciones Científicas (España), Ministerio de Economía y Competitividad (España), 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, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Work (thermodynamics) Receptor ErbB-2 Intrinsic viscosity Amino Acids Peptides and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies Monoclonal::Antibodies Monoclonal Humanized::Trastuzumab [CHEMICALS AND DRUGS] 02 engineering and technology lcsh:Chemistry Molecular dynamics Antineoplastic Agents Immunological Dinàmica molecular Diffusion (business) skin and connective tissue diseases lcsh:QH301-705.5 Spectroscopy chemistry.chemical_classification conformational fluctuations Aqueous solution Charge density General Medicine 021001 nanoscience & nanotechnology Computer Science Applications Molecular Docking Simulation Investigative Techniques::Models Theoretical::Models Molecular::Molecular Docking Simulation [ANALYTICAL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT] 0210 nano-technology aminoácidos péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales::anticuerpos monoclonales humanizados::trastuzumab [COMPUESTOS QUÍMICOS Y DROGAS] Physical Phenomena::Hydrodynamics [PHENOMENA AND PROCESSES] Protein Binding Hydrodynamic properties Globular protein Static Electricity Article Catalysis Trastuzumab/HER2 complexes Inorganic Chemistry 03 medical and health sciences fenómenos físicos::hidrodinámica [FENÓMENOS Y PROCESOS] Humans Physical and Theoretical Chemistry Molecular Biology Binding Sites Hidrodinàmica Organic Chemistry técnicas de investigación::modelos teóricos::modelos moleculares::simulación de acoplamiento molecular [TÉCNICAS Y EQUIPOS ANALÍTICOS DIAGNÓSTICOS Y TERAPÉUTICOS] Trastuzumab molecular dynamics Càncer - Simulació per ordinador Electrophoresis 030104 developmental biology chemistry lcsh:Biology (General) lcsh:QD1-999 Hydrodynamics Biophysics hydrodynamic properties Conformational fluctuations |
| Zdroj: | International Journal of Molecular Sciences Volume 20 Issue 5 International Journal of Molecular Sciences, Vol 20, Iss 5, p 1076 (2019) Digital.CSIC. Repositorio Institucional del CSIC instname Scientia Recercat. Dipósit de la Recerca de Catalunya Recercat: Dipósit de la Recerca de Catalunya Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms20051076 |
| Popis: | 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. 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 support through the Ramón y Cajal Program (MINECO, Spain)—Contract RYC-2011-09585 We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI) |
| Databáze: | OpenAIRE |
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