Optimized Protein-Excipient Interactions in the Martini 3 Force Field.

Area of Science:

• Computational Chemistry
• Biophysics
• Pharmaceutical Sciences

Background:

• High-concentration monoclonal antibody (mAb) formulations face challenges with solubility and particle formation.
• Excipients like arginine and glutamate can improve protein stability but require detailed molecular understanding.
• All-atom molecular dynamics (MD) simulations offer insights but are computationally limited for large systems.

Purpose of the Study:

• To extend the Martini 3 coarse-grained force field for accurate modeling of protein-excipient interactions in mAb formulations.
• To develop and validate new parameters for arginine and glutamate excipients using therapeutic mAb Fab domains.

Main Methods:

• Developed a novel all-atom to coarse-grained mapping for amino acid excipients, preserving zwitterionic character.
• Performed coarse-grained MD simulations using the Martini 3 force field and compared with all-atom simulations.
• Reparametrized protein-excipient interaction parameters in Martini 3 based on all-atom simulation data.

Main Results:

• Default Martini 3 parameters overestimated protein-excipient contacts, indicating excessive attraction.
• The reparametrized Martini 3 force field (Martini 3-exc) accurately reproduced protein-excipient interactions.
• New parameters closely matched all-atom simulation results for Fab-excipient interactions.

Conclusions:

• The developed Martini 3-exc force field provides a validated tool for simulating high-concentration mAb formulations.
• This advancement enables large-scale coarse-grained MD simulations to study excipient stabilizing effects.
• Improved modeling facilitates the development of more stable and effective biotherapeutic drugs.