Molecular simulation studies of human coagulation factor VIII C domain-mediated membrane binding

Jiangfeng Du, Kanin Wichapong, Tilman M. Hackeng, Gerry A. F. Nicolaes*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The C-terminal C domains of activated coagulation factor VIII (FVIIIa) are essential to membrane binding of this crucial coagulation cofactor protein. To provide an overall membrane binding mechanism for FVIII, we performed simulations of membrane binding through coarse-grained molecular dynamics simulations of the C1 and C2 domain, and the combined C-domains (C1+C2). We found that the C1 and C2 domain have different membrane binding properties. The C1 domain uses hydrophobic spikes 3 and 4, of its total of four spikes, as major loops to bind the membrane, whereas all four of its hydrophobic loops of the C2 domain appear essential for membrane binding. Interestingly, in the C1+C2 system, we observed cooperative binding of the C1 and C2 domains such that all four C2 domain spikes bound first, after which all four loops of the C1 domain inserted into the membrane, while the net binding energy was higher than that of the sum of the isolated C domains. Several residues, mutations of which are known to cause haemophilia A, were identified as key residues for membrane binding. In addition to these known residues, we identified residues from the C1 and C2 domains, which are involved in the membrane binding process, that have not been reported before as a cause for haemophilia A, but which contribute to overall membrane binding and which are likely candidates for novel causative missense mutations in haemophilia A.
Original languageEnglish
Pages (from-to)373-384
JournalThrombosis and Haemostasis
Volume113
Issue number2
DOIs
Publication statusPublished - Feb 2015

Keywords

  • Coarse-Grained Molecular Dynamics (CGMD)
  • Coagulation FVIII
  • C domains
  • membrane
  • haemophilia A

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