Abstract
Blood coagulation is a cascade of complex enzymatic reactions which involves specific proteins and cellular components to interact and prevent blood loss. The coagulation process begins by either “Tissue Dependent Pathway” (also known as extrinsic pathway) or by “contact activation pathway” (also known as intrinsic pathway). TFPI is an endogenous multivalent Kunitz type protease inhibitor which inhibits Tissue factor dependent pathway by inhibiting Tissue Factor:Factor VIIa (TF:FVIIa) complex and Factor Xa. TFPI is one of the most studied coagulation pathway inhibitor which has various clinical and potential therapeutic applications, however, its exact mechanism of inhibition is still unknown. Structure based mechanism elucidation is commonly employed technique in such cases. Therefore, in the current study the generated a complete TFPI structural model so as to understand the mechanistic details of it's functioning. The model was checked for stereochemical quality by PROCHECK-NMR, WHATIF, ProSA, and QMEAN servers. The model was selected, energy minimized and simulated for 1.5ns. The result of the study may be a guiding point for further investigations on TFPI and its role in coagulation mechanism.
Highlights
Blood coagulation pathway is a complex biological mechanism where specific proteins and cellular components interact to prevent blood loss [1]
The lowest was achieved by the ASN residue number 45 and the values were 1.356 kJ/mol, 1.397 kJ/mol, 1.528 kJ/mol and 1.414 respectively (Available with authors) The result obtained in the present study has provided a good picture of molecular dynamics of modeled TFPI
The present study generated a welldefined structure of TFPI protein and its simulation results indicate the validity of the model
Summary
Blood coagulation pathway is a complex biological mechanism where specific proteins and cellular components interact to prevent blood loss [1]. Coagulation is an important part of haemostasis. Haemostasis system allows blood to remain in fluid form in plasma and prevents excessive bleeding during vascular injury. The normal coagulation process begins with the “Tissue Dependent Pathway”, initiated by the formation of complex between Factor VIIa and Tissue Factor (TF). Blood coagulation is well regulated patho-physiologically by an important Kunitz type serine protease inhibitor known as TFPI (Tissue Factor Pathway Inhibitor). 80%) interact with the wall and rest of them circulates in plasma. TFPI is a potent inhibitor of Factor VII::TF complex and its action is regulated by the presence of Factor Xa [3]. TFPI consists of 3 Kunitz domains each having specific functions
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