Toward a Suite of Coarse-Grained Models for Molecular Simulation of Monoclonal Antibodies and Therapeutic Proteins

Abstract

A series of coarse-grained models for molecular simulation of proteins are considered, with emphasis on the application of predicting protein–protein self-interactions for monoclonal antibodies (MAbs). As an illustrative example and for quantitative comparison, the models are used to predict osmotic virial coefficients over a broad range of attractive and repulsive self-interactions and solution conditions for a series of MAbs where the second osmotic virial coefficient has been experimentally determined in prior work. The models are compared based on how well they can predict experimental behavior, their computational burdens, and scalability. An intermediate-resolution model is also introduced that can capture specific electrostatic interactions with improved efficiency and similar or improved accuracy when compared to the previously published models. Guidance is included for the selection of coarse-grained models more generally for capturing a balance of electrostatic, steric, and short-ranged nonelectrostatic interactions for proteins from low to high concentrations.

Computational models for studying physical instabilities in high concentration biotherapeutic formulations

“…More recently, Shahfar et al . 65 also compared different simplified CG models against values for five different mAbs and arrived at a similar conclusion, where domain-resolution models (e.g., a 6- or 12-bead mAb representation) are only able to reasonably predict for repulsive and mildly attractive conditions. The authors also found that a 12-bead mAb model with explicit incorporation of charged amino acids on the protein surface can reproduce for conditions dominated by attractive electrostatic interactions.…”

“… 104 , 176 Likewise, Roberts and collaborators have extensively evaluated the use of simplified CG models for capturing the behavior of on globular proteins 87 and mAbs. 15 , 65 In an initial report, Calero-Rubio et al . 15 used a series of mAb model representations (ranging from 1 to 12 CG-sites) to compare the effect of a number of physical factors and model parameters (e.g., hinge flexibility, charge distribution, and the strength of attractions) on protein–protein interactions at diluted and concentrated conditions.…”

Self-Interactions of Two Monoclonal Antibodies: Small-Angle X-ray Scattering, Light Scattering, and Coarse-Grained Modeling

“…In the early stage of development, when material availability is limited, finding a stable high concentration mAb formulation requires techniques with minimal sample consumption. Experimental techniques, such as static light scattering (LS), small-angle X-ray scattering (SAXS), and computational techniques, such as molecular dynamics simulations and Monte Carlo (MC) simulations, are widely employed to study mAb interactions. − Recently, Shahfar et al investigated the ability of models, based on different degrees of coarse-graining, to predict the experimental behavior of mAb solutions in terms of protein self-interactions and the osmotic second virial coefficient, B 22 . They showed that domain-based models can reproduce well the net repulsion between the mAbs.…”

Electrostatically Driven Protein–Protein Interactions: Quantitative Prediction of Second Osmotic Virial Coefficients to Aid Antibody Design

“…This model is termed one bead per charged site and per domain (1bC/D). 17 In this Letter, predictions from B 22 calculations using the 1bC/D model were used to propose a range of possible point mutations to reduce strong electrostatic attractions for one of the MAbs from Ferreira et al 15,16 at typical MAb formulation pH and ionic strength ranges. The candidate point mutations were either charge-to-neutral (e.g., +1 or −1 changed to zero) or charge-swap mutations (e.g., +1 to −1 or vice versa) in the wild-type (WT) MAb at pH 5.…”

“…Experimentally, the analogue to B 22 is the protein−protein Kirkwood-Buff integral (G 22 ) that is regressed from experimental SLS data or other methods such as equilibrium analytical ultracentrifugation and small-angle X-ray or neutron scattering 23−25 ) for the WT MAb and variants was calculated with previously published methods for a given choice of protein structure. 17 Given the small changes in sequence for the variants here, the value of B 22,ST was effectively the same for WT and each variant.…”