Human IgG1 Fc pH-dependent optimization from a constant pH molecular dynamics simulation analysis
The binding of IgG Fc with FcRn enables the long circulating half-life of IgG, where the Fc-FcRn complex interacts in a pH-dependent manner. This complex shows stronger interaction at pH ≤ 6.5 and weaker interaction at pH ≥ 7.4. The Fc-FcRn binding mechanism that promotes the long circulating half-l...
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Veröffentlicht in: | RSC advances 2020-03, Vol.1 (22), p.1366-1375 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | The binding of IgG Fc with FcRn enables the long circulating half-life of IgG, where the Fc-FcRn complex interacts in a pH-dependent manner. This complex shows stronger interaction at pH ≤ 6.5 and weaker interaction at pH ≥ 7.4. The Fc-FcRn binding mechanism that promotes the long circulating half-life of IgG has prompted several IgG Fc-related mutational studies to focus on the pH-dependent Fc-FcRn complex interactions in order to improve the pharmacokinetic properties of Fc. Hence, in this study, we applied the
in silico
constant pH molecular dynamics (CpHMD) simulation approach to evaluate the human Fc-FcRn complex binding (pH 6.0) and dissociating (pH 7.5) mechanism at the molecular level. The analysis showed that the protonated state of the titratable residues changes from pH 6.0 to pH 7.5, where the disrupting energy for Fc-FcRn complex formation was found to be due to the electrostatic repulsion between the complex. According to the analysis, an Fc variant was computationally designed with an improved binding affinity at pH 6.0, which is still able to dissociate at pH 7.5 with FcRn at the
in silico
level. The binding free energy calculation
via
the MMPB/GBSA approach showed that the designed Fc mutant (Mut
M4
) has increased binding affinity only at pH 6.0 compared with the reported mutant (YTE) Fc. This work demonstrates an alternative Fc design with better binding properties for FcRn, which can be useful for future experimental evaluation and validation.
An
in silico
IgG-Fc variant with better affinity at pH 6.0 but retained the dissociation at pH 7.5 was designed. |
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ISSN: | 2046-2069 2046-2069 |
DOI: | 10.1039/c9ra10712f |