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Coarse-Grained Modeling of Antibodies from Small-Angle Scattering Profiles.
Corbett, Daniel; Hebditch, Max; Keeling, Rose; Ke, Peng; Ekizoglou, Sofia; Sarangapani, Prasad; Pathak, Jai; Van Der Walle, Christopher F; Uddin, Shahid; Baldock, Clair; Avendaño, Carlos; Curtis, Robin A.
Afiliação
  • Corbett D; School of Chemical Engineering and Analytical Science, The University of Manchester , Sackville Street, Manchester, M13 9PL, U.K.
  • Hebditch M; School of Chemical Engineering and Analytical Science, The University of Manchester , Sackville Street, Manchester, M13 9PL, U.K.
  • Keeling R; School of Chemical Engineering and Analytical Science, The University of Manchester , Sackville Street, Manchester, M13 9PL, U.K.
  • Ke P; Formulation Sciences, MedImmune Ltd , Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, U.K.
  • Ekizoglou S; Formulation Sciences, MedImmune Ltd , Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, U.K.
  • Sarangapani P; Regeneron Pharmaceuticals , 777 Old Saw Mill River Road, Tarrytown, New York 10591, United States.
  • Pathak J; Vaccine Research Center, National Institute of Health , 9 West Watkins Mill Road, Suite 250, Gaithersburg, Maryland 20878, United States.
  • Van Der Walle CF; Formulation Sciences, MedImmune Ltd , Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, U.K.
  • Uddin S; Formulation Sciences, MedImmune Ltd , Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, U.K.
  • Baldock C; Division of Cell Matrix Biology and Regenerative Medicine, The University of Manchester , Oxford Road, Manchester, M13 9PT, U.K.
  • Avendaño C; School of Chemical Engineering and Analytical Science, The University of Manchester , Sackville Street, Manchester, M13 9PL, U.K.
  • Curtis RA; School of Chemical Engineering and Analytical Science, The University of Manchester , Sackville Street, Manchester, M13 9PL, U.K.
J Phys Chem B ; 121(35): 8276-8290, 2017 09 07.
Article em En | MEDLINE | ID: mdl-28796519
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Difração de Raios X / Espalhamento a Baixo Ângulo / Simulação de Dinâmica Molecular / Anticorpos Monoclonais Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Difração de Raios X / Espalhamento a Baixo Ângulo / Simulação de Dinâmica Molecular / Anticorpos Monoclonais Idioma: En Ano de publicação: 2017 Tipo de documento: Article