Molecular dynamics studies on both bound and unbound renin protease

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Natercia F Bras (Author) Other; Pedro A Fernandes (Author) FCUP; Maria J Ramos (Author) FCUP

Journal

Title: Journal of Biomolecular Structure and Dynamics

Vol. 32

Pages: 351-363

ISSN: 0739-1102

Publisher: Taylor & Francis

Indexing

ISI Web of Knowledge - 8 Citations

Scopus - 10 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-009-33J

DOI: 10.1080/07391102.2013.768553

Abstract (EN): The aspartic protease renin (REN) catalyses the rate-limiting step in the Renin-Angiotensin-Aldosterone System (RAAS), which regulates cardiovascular and renal homoeostasis in living organisms. Renin blockage is therefore an attractive therapeutic strategy for the treatment of hypertension. Herein, computational approaches were used to provide a structural characterization of the binding site, flap opening and dynamic rearrangements of REN in the key conserved residues and water molecules, with the binding of a dodecapeptide substrate or different inhibitors. All these structural insights during catalysis may assist future studies in developing novel strategies for REN inactivation. Our molecular dynamics simulations of several unbound-REN and bound-REN systems indicate similar flexible-segments plasticity with larger fluctuations in those belonging to the C-domain (exposed to the solvent). These segments are thought to assist the flap opening and closure to allow the binding of the substrate and catalytic water molecules. The unbound-REN simulation suggests that the flap can acquire three different conformations: closed, semi-open and open. Our results indicate that the semi-open conformation is already sufficient and appropriate for the binding of the angiotensinogen (Ang) tail, thus contributing to the high specificity of REN, and that both semi-open and open flap conformations are present in free and complexed enzymes. We additionally observed that the Tyr75-Trp39 H-bond has an important role in assisting flap movement, and we highlight several conserved water molecules and amino acids that are essential for the proper catalytic activity of REN.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13