The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Photo Mikael Lund

Mikael Lund

Professor

Photo Mikael Lund

Electrostatics Drive Oligomerization and Aggregation of Human Interferon Alpha-2a

Author

  • Christin Pohl
  • Marco Polimeni
  • Sowmya Indrakumar
  • Werner Streicher
  • Günther H.J. Peters
  • Allan Nørgaard
  • Mikael Lund
  • Pernille Harris

Summary, in English

Aggregation is a common phenomenon in the field of protein therapeutics and can lead to function loss or immunogenic patient responses. Two strategies are currently used to reduce aggregation: (1) finding a suitable formulation, which is labor-intensive and requires large protein quantities, or (2) engineering the protein, which requires extensive knowledge about the protein aggregation pathway. We present a biophysical characterization of the oligomerization and aggregation processes by Interferon alpha-2a (IFNα-2a), a protein drug with antiviral and immunomodulatory properties. This study combines experimental high throughput screening with detailed investigations by small-angle X-ray scattering and analytical ultracentrifugation. Metropolis Monte Carlo simulations are used to gain insight into the underlying intermolecular interactions. IFNα-2a forms soluble oligomers that are controlled by a fast pH and concentration-dependent equilibrium. Close to the isoelectric point of 6, IFNα-2a forms insoluble aggregates which can be prevented by adding salt. We show that monomer attraction is driven mainly by molecular anisotropic dipole–dipole interactions that increase with increasing pH. Repulsion is due to monopole–monopole interactions and depends on the charge of IFNα-2a. The study highlights how combining multiple methods helps to systematically dissect the molecular mechanisms driving oligomer formation and to design ultimately efficient strategies for preventing detrimental protein aggregation.

Department/s

  • Computational Chemistry
  • eSSENCE: The e-Science Collaboration

Publishing year

2021-12-23

Language

English

Pages

13657-13669

Publication/Series

Journal of Physical Chemistry B

Volume

125

Issue

50

Document type

Journal article

Publisher

The American Chemical Society (ACS)

Topic

  • Physical Chemistry (including Surface- and Colloid Chemistry)

Status

Published

ISBN/ISSN/Other

  • ISSN: 1520-6106