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

• Published in: Journal of molecular modeling 2020-03, Vol.26 (4), p.87-87, Article 87
• Main Authors: Vermeulen, Jan-G, Burt, Felicity, van Heerden, Esta, du Preez, Louis Lategan, Meiring, Muriel
• Format: Article
• Language: English
• Subjects: Blood coagulation; Chains; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Computer simulation; Crystal structure; Homology; Human tissues; In vitro methods and tests; Molecular docking; Molecular dynamics; Molecular Medicine; Original Paper; Theoretical and Computational Chemistry
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-020-4350-7

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.