caa a22 4500 445312572 CHVBK 20180317142635.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s11095-011-0503-9 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0503-9 Disulfide Scrambling in IgG2 Monoclonal Antibodies: Insights from Molecular Dynamics Simulations [Elektronische Daten] [Xiaoling Wang, Sandeep Kumar, Satish Singh] ABSTRACT: Purpose: To explore potential non-canonical disulfide linkages feasible in human IgG2 mAbs via molecular dynamics simulations of a model system, Hinge++. Methods: Hinge++ is derived from the crystal structure of a full-length murine IgG2a antibody by replacing its core hinge region with human IgG2 hinge. Fv and CH3 domains were discarded to speed up calculations. Eight independent simulations, grouped in four sets, were performed. In the control set, disulfide bonding is identical to canonical human IgG2 mAb. Different numbers of disulfide bonds were broken in the remaining three sets. Results: Two Fabs move towards Fc asymmetrically repeatedly leading to spatial proximity of LC.Cys214 and HC.Cys128 residues in one Fab with Cys residues in the upper hinge region, which could initiate disulfide scrambling. Local dynamics place the eight hinge region Cys residues in a large number of proximal positions which could facilitate non-canonical inter- and intra- heavy chain disulfide linkages in the hinge region. Conclusion: Consistent with experimental studies, our simulations indicate inter-chain disulfide linkages in human IgG2 mAbs are degenerate. Potential rational design strategies to devise hinge stabilized human IgG2 mAbs are gleaned. Springer Science+Business Media, LLC, 2011 biotherapeutics nationallicence hinge nationallicence immunoglobulin nationallicence molecular modeling nationallicence structure nationallicence CDR : complementarity-determining region nationallicence Fab : fragment antigen binding nationallicence Fc : fragment crystallizable nationallicence HC : heavy chain nationallicence LC : light chain nationallicence mAb : monoclonal antibody nationallicence MD : molecular dynamics nationallicence PDB : protein data bank nationallicence RMSD : root mean squared deviation nationallicence Wang Xiaoling Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut Kumar Sandeep Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut Singh Satish Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/12(2011-12-01), 3128-3144 0724-8741 28:12<3128 2011 28 11095 https://doi.org/10.1007/s11095-011-0503-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0503-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wang Xiaoling Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut NATIONALLICENCE 700 1- Kumar Sandeep Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut NATIONALLICENCE 700 1- Singh Satish Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/12(2011-12-01), 3128-3144 0724-8741 28:12<3128 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer