Issue 3, 2016

In silico based investigation of dynamic variations in neprilysin (NEP and NEP2) proteins for extracting the point of specificity

Abstract

Neprilysin-2 (NEP2) in the central nervous system controls Alzheimer’s protein (amyloid-β) deposition, and prevents its occurrence. However, in the peripheral system, its closest homolog, neutral endopeptidase (NEP), regulates hypertension and heart related diseases. Inhibitors of NEP with a lesser degree of specificity can treat hypertension with an increased risk of cerebral deposition of amyloid-β. In order to rationalize the point of selectivity, the dynamic behavior of human NEP and NEP2 proteins was monitored by conducting molecular dynamics (MD) simulations. A computationally reliable model of NEP2 was achieved with 79.9%, 19.1% and 0.2% residues in the allowed, additionally allowed and disallowed regions respectively, using 1DMT as a reference protein. Additionally, molecular docking studies were carried out for a set of five already known inhibitors of NEP and modeled NEP2 to obtain the comparative behaviors of the complexes. MD results highlighted their different responses along with important residues having a part in ligand–protein binding. For substrate and inhibitor binding, Arg664/661 and Zn697/694 were identified as the most conserved residues. High degree flexible transitions during the MD simulations were also observed in loop areas along with active site residues. Energy calculations, hydrogen bonds and their occupancy rates helped to conclude each ligand's potency towards a particular target. In most complexes of hNEP2, the ligands showed weak interactions which might be due to its larger pocket size or huge conformational variations in active site residues upon complexation. In the case of inhibitors of a small size like thiorphan, Arg49 and Arg664 are found to be acting to support the ligand binding in NEP while only Arg661 is acting in NEP2.

Graphical abstract: In silico based investigation of dynamic variations in neprilysin (NEP and NEP2) proteins for extracting the point of specificity

Article information

Article type
Paper
Submitted
28 Oct 2015
Accepted
25 Jan 2016
First published
05 Feb 2016

Mol. BioSyst., 2016,12, 1024-1036

Author version available

In silico based investigation of dynamic variations in neprilysin (NEP and NEP2) proteins for extracting the point of specificity

Z. Ul-Haq, S. Usmani, S. Iqbal and S. R. Zia, Mol. BioSyst., 2016, 12, 1024 DOI: 10.1039/C5MB00727E

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