367
Views
9
CrossRef citations to date
0
Altmetric
Research Articles

Molecular dynamics simulations of human α-thrombin in different structural contexts: evidence for an aptamer-guided cooperation between the two exosites

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 2199-2209 | Received 20 Jan 2020, Accepted 16 Mar 2020, Published online: 07 Apr 2020
 

Abstract

Human α-thrombin (thrombin) is a multifunctional enzyme that plays a pivotal role in the coagulation pathway. Thrombin activity can be effectively modulated by G-quadruplex-based oligonucleotide aptamers that specifically interact with the two positively charged regions (exosites I and II) on the protein surface. Although insightful atomic-level snapshots of the recognition between thrombin and aptamers have been recently achieved through crystallographic analyses, some dynamic aspects of this interaction have not been fully characterized. We here report molecular dynamics simulations of thrombin in different association states: ligand-free and binary/ternary complexes with the aptamers TBA (at exosite I) and HD22_27mer (at exosite II). The simulations carried out on the binary and ternary complexes formed by thrombin with these aptamers provide a dynamic view of the interactions that stabilize them in a crystal-free environment. Interestingly, the analysis of the dynamics of the exosites in different thrombin binding states clearly indicates that the HD22_27mer binding at the exosite II favours conformations of exosite I that are prone to the TBA binding. Similar effects are observed upon the binding of TBA to the exosite I. These observations provide an atomic-level picture of the exosite inter-communication in thrombin and explain the experimentally detected cooperativity of the TBA/HD22_27mer binding.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Acknowledgements

CINECA Supercomputing (framework ISCRA@CINECA - project code HP10C8CHST) is acknowledged for computational support.

Disclosure statement

The authors declare no conflicts of interest.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.