The efficiency of protease inhibiting drugs is hampered by the rapid emergence of protease variants. Understanding this phenomenon requires the characterization of the salient steps of HIV-1 protease's catalytic cycle. We summarize our investigations on the reactive geometry of the protease-substrate complex based on first principles, QM/MM and cla ssical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local struct ural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concert ed large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeti ng HIV-1 protease. We further present computational studies on HIV-1 transactivator of transcription (Tot) viral RNA binding protein. Interfering with Tat/TAR interactions is a promising strategy for anti-AIDS intervention. We have identified conserved structural and energetic features among different protein isolates and predicted the structural d eterminants of Tat in complex with one of the host cell cognate proteins, p/CAF. These findings may help the design of ligands interfering with Tat function.

Multi-scale modeling of HIV-1 proteins / Carnevale, V; Raugei, S; Neri, M; Pantano, S; Micheletti, Cristian; Carloni, P.. - In: JOURNAL OF MOLECULAR STRUCTURE. THEOCHEM. - ISSN 0166-1280. - 898:(2009), pp. 97-105. [10.1016/j.theochem.2008.11.028]

Multi-scale modeling of HIV-1 proteins

Micheletti, Cristian;
2009-01-01

Abstract

The efficiency of protease inhibiting drugs is hampered by the rapid emergence of protease variants. Understanding this phenomenon requires the characterization of the salient steps of HIV-1 protease's catalytic cycle. We summarize our investigations on the reactive geometry of the protease-substrate complex based on first principles, QM/MM and cla ssical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local struct ural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concert ed large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeti ng HIV-1 protease. We further present computational studies on HIV-1 transactivator of transcription (Tot) viral RNA binding protein. Interfering with Tat/TAR interactions is a promising strategy for anti-AIDS intervention. We have identified conserved structural and energetic features among different protein isolates and predicted the structural d eterminants of Tat in complex with one of the host cell cognate proteins, p/CAF. These findings may help the design of ligands interfering with Tat function.
2009
898
97
105
Carnevale, V; Raugei, S; Neri, M; Pantano, S; Micheletti, Cristian; Carloni, P.
File in questo prodotto:
File Dimensione Formato  
THEOCH11401.pdf

non disponibili

Licenza: Non specificato
Dimensione 792.09 kB
Formato Adobe PDF
792.09 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

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: https://hdl.handle.net/20.500.11767/13089
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 4
social impact