Issue 12, 2014

Computational study of the structural plasticity and the ligand binding affinity of the IRES subdomain IIa

Abstract

The internal ribosome entry site (IRES) of hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. In order to fulfil its role in HCV translation initiation its subdomain IIa should adopt an L-shaped conformation. However, according to the present knowledge, the bent topology of IIa would prevent the progression of the ribosome from initiation to productive translation. In order to be released from the ribosome, IIa should transform from the bended to an extended form. With the purpose to study the plasticity and stability of the IRES subdomain IIa we performed detailed molecular dynamics (MD) simulations of the ligand free RNA and its (native and mutated) complexes with the potential HCV inhibitors. We have shown that upon ligand removal conformation of the IIa subdomain changed from an extended into an L-shaped one during several tens of ns. Differently, binding of the benzimidazole translation inhibitors locked IIa in the extended conformation. On the other hand, the newly discovered translation inhibitor diaminopiperidine (DAP), in agreement with the experimentally based assumptions, stabilized IIa RNA in the bent conformation during MD simulations. Apparently the efficient locking of subdomain IIa in one form is one of the requirements the HCV RNA targeting drugs should fulfil.

Graphical abstract: Computational study of the structural plasticity and the ligand binding affinity of the IRES subdomain IIa

Supplementary files

Article information

Article type
Paper
Submitted
06 Aug 2014
Accepted
25 Sep 2014
First published
25 Sep 2014

Mol. BioSyst., 2014,10, 3272-3279

Author version available

Computational study of the structural plasticity and the ligand binding affinity of the IRES subdomain IIa

M. G. Branilović and S. Tomić, Mol. BioSyst., 2014, 10, 3272 DOI: 10.1039/C4MB00469H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements