Molecular Dynamics Simulation of the Crystallizable Fragment of IgG1—Insights for the Design of Fcabs

International Journal of Molecular Sciences

Balder Lai¹  Christoph Hasenhindl²  Christian Obinger² 

[1] 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; E-Mail:;Department of Chemistry, Division of Biochemistry, VIBT (Vienna Institute of BioTechnology), BOKU (University of Natural Resources and Life Sciences), Vienna A-1190, Austria; E-Mails:

关键词: molecular dynamics simulations;    molecular modeling;    crystallizable Fc fragment;    monoclonal antibody;   

DOI  :  10.3390/ijms15010438

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland