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Molecular Dynamics Simulation of the Crystallizable Fragment of IgG1—Insights for the Design of Fcabs
Department of Material Sciences and Process Engineering, Institute of Molecular Modeling and Simulation, BOKU (University of Natural Resources and Life Sciences), Vienna A-1190, Austria
Department of Chemistry, Division of Biochemistry, VIBT (Vienna Institute of BioTechnology), BOKU (University of Natural Resources and Life Sciences), Vienna A-1190, Austria
* Author to whom correspondence should be addressed.
Received: 28 November 2013; in revised form: 19 December 2013 / Accepted: 27 December 2013 / Published: 2 January 2014
Abstract: An interesting format in the development of therapeutic monoclonal antibodies uses the crystallizable fragment of IgG1 as starting scaffold. Engineering of its structural loops allows generation of an antigen binding site. However, this might impair the molecule’s conformational stability, which can be overcome by introducing stabilizing point mutations in the CH3 domains. These point mutations often affect the stability and unfolding behavior of both the CH2 and CH3 domains. In order to understand this cross-talk, molecular dynamics simulations of the domains of the Fc fragment of human IgG1 are reported. The structure of human IgG1-Fc obtained from X-ray crystallography is used as a starting point for simulations of the wild-type protein at two different pH values. The stabilizing effect of a single point mutation in the CH3 domain as well as the impact of the hinge region and the glycan tree structure connected to the CH2 domains is investigated. Regions of high local flexibility were identified as potential sites for engineering antigen binding sites. Obtained data are discussed with respect to the available X-ray structure of IgG1-Fc, directed evolution approaches that screen for stability and use of the scaffold IgG1-Fc in the design of antigen binding Fc proteins.
Keywords: molecular dynamics simulations; molecular modeling; crystallizable Fc fragment; monoclonal antibody
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Lai, B.; Hasenhindl, C.; Obinger, C.; Oostenbrink, C. Molecular Dynamics Simulation of the Crystallizable Fragment of IgG1—Insights for the Design of Fcabs. Int. J. Mol. Sci. 2014, 15, 438-455.
Lai B, Hasenhindl C, Obinger C, Oostenbrink C. Molecular Dynamics Simulation of the Crystallizable Fragment of IgG1—Insights for the Design of Fcabs. International Journal of Molecular Sciences. 2014; 15(1):438-455.
Lai, Balder; Hasenhindl, Christoph; Obinger, Christian; Oostenbrink, Chris. 2014. "Molecular Dynamics Simulation of the Crystallizable Fragment of IgG1—Insights for the Design of Fcabs." Int. J. Mol. Sci. 15, no. 1: 438-455.