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

Mahapatra, Sujata; Polimeni, Marco; Gentiluomo, Lorenzo; Roessner, Dierk; Frieß, Wolfgang; Peters, Günther H.J.; Streicher, Werner; Lund, Mikael; Harris, Pernille

doi:10.1021/acs.molpharmaceut.1c00627

Cited by 6 publications

(5 citation statements)

References 55 publications

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“…Including excipients in simulations may also require additional force field development of these molecules in the coarse-grained presentation. CG simulations have been applied to investigate self-interactions of antibodies [66] , [67] , where the antibody is usually coarse-grained to much smaller beads (6–12 beads) [66] , or the self-association is monitored by simulating only two antibodies [67] .…”

Section: Resultsmentioning

confidence: 99%

Investigation of the pH-dependent aggregation mechanisms of GCSF using low resolution protein characterization techniques and advanced molecular dynamics simulations

Ko¹,

Berner²,

Kulakova³

et al. 2022

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

Investigation of the pH-dependent aggregation mechanisms of GCSF using low resolution protein characterization techniques and advanced molecular dynamics simulations

Ko¹,

Berner²,

Kulakova³

et al. 2022

Computational and Structural Biotechnology Journal

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“…With the amino-acid-based coarse-grained model, we perform Metropolis-Hastings Monte Carlo (MC) simulations of the mAb solution using Faunus (v2.9.1 git 3edf85cf), 18 which is a software allowing for several types of MC simulations, to estimate the mAb charge distribution (as performed here 19 ). In particular, we carry out constant-pH MC simulations with a single rigid mAb and titration moves only, 20 which allow the amino-acid charges to fluctuate and to reach an equilibrium distribution at a given pH and the ionic strength.…”

Section: Methodsmentioning

confidence: 99%

A multi-scale numerical approach to study monoclonal antibodies in solution

Polimeni,

Zaccarelli,

Gulotta

et al. 2024

APL Bioengineering

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Developing efficient and robust computational models is essential to improve our understanding of protein solution behavior. This becomes particularly important to tackle the high-concentration regime. In this context, the main challenge is to put forward coarse-grained descriptions able to reduce the level of detail, while retaining key features and relevant information. In this work, we develop an efficient strategy that can be used to investigate and gain insight into monoclonal antibody solutions under different conditions. We use a multi-scale numerical approach, which connects information obtained at all-atom and amino-acid levels to bead models. The latter has the advantage of reproducing the properties of interest while being computationally much faster. Indeed, these models allow us to perform many-protein simulations with a large number of molecules. We can, thus, explore conditions not easily accessible with more detailed descriptions, perform effective comparisons with experimental data up to very high protein concentrations, and efficiently investigate protein–protein interactions and their role in phase behavior and protein self-assembly. Here, a particular emphasis is given to the effects of charges at different ionic strengths.

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“…Based on this structure and using the same protocol as in ref , we construct a coarse-grained representation of the mAb by replacing each amino acid with a spherical bead of diameter σ normalb normale normala normald normala normala = ( 6 M W , normala normala / π ρ ) 1 / 3 , where M W,aa is the amino acid molecular weight (in g mol –1 ), ρ = 1 (in g mol –1 Å –3 ) is an average amino acid density, and the suffix aa stands for “amino acid”. With the amino-acid-based coarse-grained model, we perform Metropolis-Hastings Monte Carlo (MC) simulations of the mAb solution using Faunus, which is software allowing for several types of MC simulations, in order to estimate the mAb net charge Z calc and the charge distribution (as performed here).…”

Section: Methodsmentioning

confidence: 99%

Combining Scattering Experiments and Colloid Theory to Characterize Charge Effects in Concentrated Antibody Solutions

Gulotta,

Polimeni,

Lenton

et al. 2024

Mol. Pharmaceutics

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Charges and their contribution to protein−protein interactions are essential for the key structural and dynamic properties of monoclonal antibody (mAb) solutions. In fact, they influence the apparent molecular weight, the static structure factor, the collective diffusion coefficient, or the relative viscosity, and their concentration dependence. Further, charges play an important role in the colloidal stability of mAbs. There exist standard experimental tools to characterize mAb net charges, such as the measurement of the electrophoretic mobility, the second virial coefficient, or the diffusion interaction parameter. However, the resulting values are difficult to directly relate to the actual overall net charge of the antibody and to theoretical predictions based on its known molecular structure. Here, we report the results of a systematic investigation of the solution properties of a charged IgG1 mAb as a function of concentration and ionic strength using a combination of electrophoretic measurements, static and dynamic light scattering, small-angle X-ray scattering, and tracer particle-based microrheology. We analyze and interpret the experimental results using established colloid theory and coarse-grained computer simulations. We discuss the potential and limits of colloidal models for the description of the interaction effects of charged mAbs, in particular pointing out the importance of incorporating shape and charge anisotropy when attempting to predict structural and dynamic solution properties at high concentrations.

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

Cited by 6 publications

References 55 publications

Investigation of the pH-dependent aggregation mechanisms of GCSF using low resolution protein characterization techniques and advanced molecular dynamics simulations

Investigation of the pH-dependent aggregation mechanisms of GCSF using low resolution protein characterization techniques and advanced molecular dynamics simulations

A multi-scale numerical approach to study monoclonal antibodies in solution

Combining Scattering Experiments and Colloid Theory to Characterize Charge Effects in Concentrated Antibody Solutions

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