Optimized Protein–Excipient Interactions in the Martini 3 Force Field DOI
Tobias M. Prass, Kresten Lindorff‐Larsen, Patrick Garidel

et al.

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

The high doses of drugs required for biotherapeutics, such as monoclonal antibodies (mAbs), and the small volumes that can be administered to patients by subcutaneous injections pose challenges due high-concentration formulations. addition excipients, arginine glutamate, protein formulations increase solubility reduce tendency particle formation. Molecular dynamics (MD) simulations provide microscopic insights into mode action excipients in mAb but require large system sizes long time scales are currently beyond reach at fully atomistic level. Computationally efficient coarse-grained models Martini 3 force field tackle this challenge careful parametrization, testing, validation. This study extends popular toward realistic protein–excipient interactions glutamate using Fab domains therapeutic mAbs trastuzumab omalizumab model systems. A novel all-atom mapping amino acid is introduced, which explicitly captures zwitterionic character backbone. Fab–excipient characterized concerning molecular contacts with Fabs single-residue compared results from a reference. Our findings reveal an overestimation default interaction parameters 3, suggesting too strong attraction between residues excipients. Therefore, we reparametrized against simulations. excipient obtained new Lennard-Jones (LJ) parameters, coined 3-exc, agree closely reference data. work presents improved parameter set mAb-arginine mAb-glutamate field, key step large-scale MD stabilizing effects

Language: Английский

Optimized Protein–Excipient Interactions in the Martini 3 Force Field DOI
Tobias M. Prass, Kresten Lindorff‐Larsen, Patrick Garidel

et al.

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

The high doses of drugs required for biotherapeutics, such as monoclonal antibodies (mAbs), and the small volumes that can be administered to patients by subcutaneous injections pose challenges due high-concentration formulations. addition excipients, arginine glutamate, protein formulations increase solubility reduce tendency particle formation. Molecular dynamics (MD) simulations provide microscopic insights into mode action excipients in mAb but require large system sizes long time scales are currently beyond reach at fully atomistic level. Computationally efficient coarse-grained models Martini 3 force field tackle this challenge careful parametrization, testing, validation. This study extends popular toward realistic protein–excipient interactions glutamate using Fab domains therapeutic mAbs trastuzumab omalizumab model systems. A novel all-atom mapping amino acid is introduced, which explicitly captures zwitterionic character backbone. Fab–excipient characterized concerning molecular contacts with Fabs single-residue compared results from a reference. Our findings reveal an overestimation default interaction parameters 3, suggesting too strong attraction between residues excipients. Therefore, we reparametrized against simulations. excipient obtained new Lennard-Jones (LJ) parameters, coined 3-exc, agree closely reference data. work presents improved parameter set mAb-arginine mAb-glutamate field, key step large-scale MD stabilizing effects

Language: Английский

Citations

0