Dataset Information

Molecular Dynamics Simulations Reveal Interactions of an IgG1 Antibody With Selected Fc Receptors.

ABSTRACT: In a survey of novel interactions between an IgG1 antibody and different Fcγ receptors (FcγR), molecular dynamics simulations were performed of interactions of monoclonal antibody involved complexes with FcγRs. Free energy simulations were also performed of isolated wild-type and substituted Fc regions bound to FcγRs with the aim of assessing their relative binding affinities. Two different free energy calculation methods, Molecular Mechanical/Generalized Born Molecular Volume (MM/GBMV) and Bennett Acceptance Ratio (BAR), were used to evaluate the known effector substitution G236A that is known to selectively increase antibody dependent cellular phagocytosis. The obtained results for the MM/GBMV binding affinity between different FcγRs are in good agreement with previous experiments, and those obtained using the BAR method for the complete antibody and the Fc-FcγR simulations show increased affinity across all FcγRs when binding to the substituted antibody. The FcγRIIa, a key determinant of antibody agonistic efficacy, shows a 10-fold increase in binding affinity, which is also consistent with the published experimental results. Novel interactions between the Fab region of the antibody and the FcγRs were discovered with this in silico approach, and provide insights into the antibody-FcγR binding mechanism and show promise for future improvements of therapeutic antibodies for preclinical studies of biological drugs.

SUBMITTER: Kralj S

PROVIDER: S-EPMC8283507 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Antibody-dependent cellular cytotoxicity (ADCC) is an important effector function determining the clinical efficacy of therapeutic antibodies. Core fucose removal from N-glycans on the Fc portion of immunoglobulin G (IgG) improves the binding affinity for Fc? receptor IIIa (Fc?RIIIa) and dramatically enhances ADCC. Our previous structural analyses revealed that Tyr-296 of IgG1-Fc plays a critical role in the interaction with Fc?RIIIa, particularly in the enhanced Fc?RIIIa binding of nonfucosylated IgG1. However, the importance of the Tyr-296 residue in the antibody in the interaction with various Fc? receptors has not yet been elucidated. To further clarify the biological importance of this residue, we established comprehensive Tyr-296 mutants as fucosylated and nonfucosylated anti-CD20 IgG1s rituximab variants and examined their binding to recombinant soluble human Fc? receptors: shFc?RI, shFc?RIIa, shFc?RIIIa, and shFc?RIIIb. Some of the mutations affected the binding of antibody to not only shFc?RIIIa but also shFc?RIIa and shFc?RIIIb, suggesting that the Tyr-296 residue in the antibody was also involved in interactions with Fc?RIIa and Fc?RIIIb. For Fc?RIIIa binding, almost all Tyr-296 variants showed lower binding affinities than the wild-type antibody, irrespective of their core fucosylation, particularly in Y296K and Y296P. Notably, only the Y296W mutant showed improved binding to Fc?RIIIa. The 3.00 Å-resolution crystal structure of the nonfucosylated Y296W mutant in complex with shFc?RIIIa harboring two N-glycans revealed that the Tyr-to-Trp substitution increased the number of potential contact atoms in the complex, thus improving the binding of the antibody to shFc?RIIIa. The nonfucosylated Y296W mutant retained high ADCC activity, relative to the nonfucosylated wild-type IgG1, and showed greater binding affinity for Fc?RIIa. Our data may improve our understanding of the biological importance of human IgG1-Fc Tyr-296 in interactions with various Fc? receptors, and have applications in the modulation of the IgG1-Fc function of therapeutic antibodies.

Dataset Information

Molecular Dynamics Simulations Reveal Interactions of an IgG1 Antibody With Selected Fc Receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets