Study of the interaction between a novel, protein-stabilizing dipeptide and Interferon-alpha-2a by construction of a Markov state model from molecular dynamics simulations

Andreas Tosstorff*, Günther H.J. Peters, Gerhard Winter

*Corresponding author for this work

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Abstract

We recently reported the discovery of a novel protein stabilizing dipeptide, glycyl-D-asparagine, through a structure-based approach. As the starting hypothesis leading to the discovery, we postulated a stabilizing effect achieved by binding of the dipeptide to an aggregation prone region on the protein's surface. Here we present a detailed study of the interaction mechanism between the dipeptide and Interferon-alpha-2A (IFN) through the construction of a Markov state model from molecular dynamics trajectories. We identify multiple binding sites and compare these to aggregation prone regions. Additionally, we calculate the lifetime of the protein-excipient complex. If the excipient remained bound to IFN after administration, it could alter the protein's therapeutic efficacy. We establish that the lifetime of the complex between IFN and glycyl-D-asparagine is extremely short. Under these circumstances, stabilization by stoichiometric binding is consequently no impediment for a safe use of an excipient.

Original languageEnglish
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume149
Pages (from-to)105-112
ISSN0939-6411
DOIs
Publication statusPublished - 2020

Keywords

  • Excipient
  • Interferon-alpha-2a
  • Markov state model
  • Protein aggregation
  • Protein formulation

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