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Coarse-Grained Modeling of Antibodies from Small-Angle Scattering Profiles

DOI: 10.1021/acs.jpcb.7b04621 DOI Help

Authors: Daniel Corbett (The University of Manchester) , Max Hebditch (The University of Manchester) , Rose Keeling (The University of Manchester) , Peng Ke (MedImmune Ltd) , Sofia Ekizoglou (MedImmune Ltd) , Prasad Sarangapani (Regeneron Pharmaceuticals) , Jai Pathak (National Institute of Health) , Christopher F. Van Der Walle (MedImmune Ltd) , Shahid Uddin (MedImmune Ltd) , Clair Baldock (The University of Manchester) , Carlos Avendaño (The University of Manchester) , Robin A. Curtis (The University of Manchester)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: The Journal Of Physical Chemistry B , VOL 121 , PAGES 8276 - 8290

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 10510

Abstract: Predicting the concentrated solution behavior for monoclonal antibodies requires developing and using minimal models to describe their shape and interaction potential. Toward this end, the small-angle X-ray scattering (SAXS) profiles for a monoclonal antibody (COE-03) have been measured under solution conditions chosen to produce weak self-association. The experiments are complemented with molecular simulations of a three-bead antibody model with and without interbead attraction. The scattering profile is extracted directly from the molecular simulation to avoid using the decoupling approximation. We examine the ability of the three-bead model to capture features of the scattering profile and the dependence of compressibilty on protein concentration. The three-bead model is able to reproduce generic features of the experimental structure factor as a function of wave vector S(k) including a well-defined shoulder, which is a consequence of the planar structure of the antibody, and a well-defined minimum in S(k) at k ∼ 0.025 Å–1. We also show the decoupling approximation is incapable of accounting for highly anisotropic shapes. The best-fit parameters obtained from matching spherical models to simulated scattering profiles are protein concentration dependent, which limits their applicability for predicting thermodynamic properties. Nevertheless, the experimental compressibility curves can be accurately reproduced by an appropriate parametrization of the Baxter adhesive model, indicating the model provides a semiempirical equation of state for the antibody. The results provide insights into how equations of state can be improved for antibodies by accounting for their anisotropic shapes.

Subject Areas: Biology and Bio-materials, Chemistry, Physics


Instruments: B21-High Throughput SAXS

Added On: 05/12/2017 15:59

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