Characterization of the inhibition mechanism of a tissuefactor inhibiting single-chain variable fragment: a combined computational approach.

Autor: Vermeulen JG; Department of Microbial, Biochemical and Food Biotechnology, Faculty of Agricultural Sciences, University of the Free State, Bloemfontein, South Africa. VermeulenJ@ufs.ac.za.; Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa. VermeulenJ@ufs.ac.za., Burt F; Division of Virology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.; National Health Laboratory Service, Universitas, Bloemfontein, South Africa., van Heerden E; Department of Microbial, Biochemical and Food Biotechnology, Faculty of Agricultural Sciences, University of the Free State, Bloemfontein, South Africa., du Preez LL; Department of Microbial, Biochemical and Food Biotechnology, Faculty of Agricultural Sciences, University of the Free State, Bloemfontein, South Africa., Meiring M; Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.; National Health Laboratory Service, Universitas, Bloemfontein, South Africa.
Jazyk: angličtina
Zdroj: Journal of molecular modeling [J Mol Model] 2020 Mar 26; Vol. 26 (4), pp. 87. Date of Electronic Publication: 2020 Mar 26.
DOI: 10.1007/s00894-020-4350-7
Abstrakt: The interaction of a single-chain variable fragment (scFv) directed against human tissue factor (TF) was predicted using an in silico approach with the aim to establish a most likely mechanism of inhibition. The structure of the TF inhibiting scFv (TFI-scFv) was predicted using homology modeling, and complementarity-determining regions (CDRs) were identified. The CDR was utilized to direct molecular docking between the homology model of TFI-scFv and the crystal structure of the extracellular domains of human tissue factor. The rigid-body docking model was refined by means of molecular dynamic (MD) simulations, and the most prevalent cluster was identified. MD simulations predicted improved interaction between TFI-scFv and TF and propose the formation of stable complex for duration of the 600-ns simulation. Analysis of the refined docking model suggests that the interactions between TFI-scFv would interfere with the allosterical activation of coagulation factor VII (FVII) by TF. This interaction would prevent the formation of the active TF:VIIa complex and in so doing inhibit the initiation phase of blood coagulation as observers during in vitro testing.
Databáze: MEDLINE
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