Monoclonal antibodies (mAbs) represent one of the most innovative class of biopharmaceuticals, due the ability of their Fab portion to specifically recognize unique epitopes on the target molecule. mAbs can also act as stimulators of immune and anti-inflammatory reactions, like Antibody-Dependent Cell Cytotoxicity (ADCC), Complement-Dependent Cytotoxicity (CDC) and Antibody-Dependent Cell Phagocytosis (ADCP), which are determined by the interaction between Fc portion and its receptors and may depend upon glycosylation. Assessment of Fc effector functions is therefore a critical step for pharmaceutical companies. In silico structural investigation could be a powerful tool to clarify the role of different glycan patterns in the recognition mechanism of Fc::FcRs complexes. The whole atomistic structure of mAb1 was built by chimeric homology modeling, performed by MOE suite (Molecular Operating Environment). Then, the impact of a fucose core on a representative IgG1 structure is currently under investigation through molecular dynamics (MD) simulations, in three different models: aglycosylated mAb, glycosylated-fucosylated (G0F), and glycosylated-afucosylated (G0). All the MD calculations are carried out by NAMD 2.13 package handled by MOE graphical interface. A first MD simulation was performed on the aglycosylated mAb in an explicit solvent model with AMBER10:EHT forcefield for 100 ns. Preliminary analysis of the trajectory revealed that the mAb reaches an equilibrium state after 50 ns of simulation, suggesting a good stability of the protein in our system. Ongoing simulations of fucosylated and afucosylated models will be useful for clarifying the impact of different glycosylation patterns on mAbs tertiary and quaternary structure. In parallel, to consolidate our results as well as to validate the use of the forcefield for glycan treatments, results from MD simulations performed on both the single G0F and G0 glycan chains in a water box will be compared with experimental data. These data may pave the way for the understanding of molecular basis of Fc::FcRs recognition and of the impact of different glycosylation patterns on this interaction.
|Titolo:||IgG1 Effecor functions: elucidation of glycans role by in silico structural analysis|
|Data di pubblicazione:||4-giu-2019|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Citazione:||IgG1 Effecor functions: elucidation of glycans role by in silico structural analysis / S. Saporiti, C. Parravicini, F. Centola, C. Pergola, I. Eberini. ((Intervento presentato al convegno Riunione dei dottorandi in discipline biochimiche tenutosi a Brallo di Pregola nel 2019.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|