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Binding modes of prothrombin cleavage site sequences to the factor Xa catalytic triad: Insights from atomistic simulations
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Theoretical Chemistry and Biology. Zhejiang Univ, Dept Chem, Hangzhou 310027, Peoples R China..
Zhejiang Univ, Dept Chem, Hangzhou 310027, Peoples R China..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
2022 (English)In: Computational and Structural Biotechnology Journal, E-ISSN 2001-0370, Vol. 20, p. 5401-5408Article in journal (Refereed) Published
Abstract [en]

Prothrombin is a key zymogen of the coagulation process and can be converted to thrombin by the prothrombinase complex, which consists of factor Xa (FXa), cofactor Va (FVa), and phospholipids. Prothrombin can be activated at two cleavage sites, R271 and R320, which generates two intermediates: prethrombin-2 via the initial cleavage at R271, and meizothrombin via the first cleavage at R320. Several mechanisms have been proposed to explain this activation preference, but the role of cleavage site sequences in prothrombin activation has not been thoroughly investigated. Here, we used an advanced sampling technique, parallel tempering metadynamics with a well-tempered ensemble (PTMetaDWTE), to study the binding modes of prothrombin cleavage site sequences R266AIEGRTATSEY277 (denoted as Pep271) and S315YIDGRIVEGSD326 (denoted as Pep320) to the FXa catalytic triad. Our study indicates that there exist three binding modes for Pep271 to the FXa catalytic triad but only one binding mode for Pep320 to the FXa catalytic triad. Further molecular dynamics simulations revealed that due to the strong electrostatic interactions, especially the H-bond interactions and salt bridges formed between Pep320 and FXa, the binding mode in the Pep320-FXa system is more stable than the binding modes in the Pep271-FXa system. In view of experimental observations and our results that there exists only one binding mode for Pep320 to the FXa catalytic triad and especially R320 in Pep320 can stably bind to the FXa catalytic triad, we believe that the first cleavage at R320 is favored.

Place, publisher, year, edition, pages
Elsevier BV , 2022. Vol. 20, p. 5401-5408
Keywords [en]
Prothrombin activation, Factor Xa, Molecular dynamics simulation
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-321907DOI: 10.1016/j.csbj.2022.09.030ISI: 000874658200004PubMedID: 36212544Scopus ID: 2-s2.0-85139071286OAI: oai:DiVA.org:kth-321907DiVA, id: diva2:1716653
Note

QC 20221206

Available from: 2022-12-06 Created: 2022-12-06 Last updated: 2022-12-06Bibliographically approved

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Li, JiachenTu, Yaoquan

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