The binding mechanism of HIV-1 protease monomers leading to the catalytically competent dimeric enzyme has been investigated by means of state-of-the-art atomistic simulations. The emerging picture allows a deeper understanding of experimental observations and reveals that water molecules trapped at the interface have an important role in slowing down the kinetics of the association process. Unexpectedly, a cryptic binding pocket is identified at the interface of the complex, corresponding to a partially bound dimer that lacks enzymatic function. The pocket has a transient nature with a lifetime longer than 1 μs, and it displays very favorable druggability features. Docking as well as MM-GBSA free-energy calculations further support the possibility to target the new binding site by means of inhibitors able to prevent the complete dimerization by capturing the inactive conformation. This discovery could open the way to the rational design of a new class of anti-HIV drugs.

HIV-1 protease dimerization dynamics reveals a transient druggable binding pocket at the interface

PIETRUCCI, FABIO;VARGIU, ATTILIO VITTORIO;
2015

Abstract

The binding mechanism of HIV-1 protease monomers leading to the catalytically competent dimeric enzyme has been investigated by means of state-of-the-art atomistic simulations. The emerging picture allows a deeper understanding of experimental observations and reveals that water molecules trapped at the interface have an important role in slowing down the kinetics of the association process. Unexpectedly, a cryptic binding pocket is identified at the interface of the complex, corresponding to a partially bound dimer that lacks enzymatic function. The pocket has a transient nature with a lifetime longer than 1 μs, and it displays very favorable druggability features. Docking as well as MM-GBSA free-energy calculations further support the possibility to target the new binding site by means of inhibitors able to prevent the complete dimerization by capturing the inactive conformation. This discovery could open the way to the rational design of a new class of anti-HIV drugs.
Binding sites; Crystallography, X-Ray; Darunavir; HIV protease; HIV protease inhibitors; Humans; Kinetics; Models, molecular; Protein binding; Protein conformation; Pyridines; Pyrones; Thermodynamics; Protein multimerization; Multidisciplinary
File in questo prodotto:
File Dimensione Formato  
HIV_transient_site_SciRep_2015.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: versione editoriale
Dimensione 2.07 MB
Formato Adobe PDF
2.07 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/195419
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 14
social impact