The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457-5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding.

Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA / Musiani, Francesco; Rossetti, G.; Capece, L.; Gerger, T. M.; Micheletti, Cristian; Varani, G.; Carloni, P.. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - 136:44(2014), pp. 15631-15637. [10.1021/ja507812v]

Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA

Musiani, Francesco;Micheletti, Cristian;
2014-01-01

Abstract

The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457-5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding.
2014
136
44
15631
15637
https://www.ncbi.nlm.nih.gov/pubmed/25313638
Musiani, Francesco; Rossetti, G.; Capece, L.; Gerger, T. M.; Micheletti, Cristian; Varani, G.; Carloni, P.
File in questo prodotto:
File Dimensione Formato  
JACS_2014_Tar_Musiani_et_al.pdf

non disponibili

Tipologia: Versione Editoriale (PDF)
Licenza: Non specificato
Dimensione 2.14 MB
Formato Adobe PDF
2.14 MB 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/20.500.11767/12282
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 27
  • ???jsp.display-item.citation.isi??? 27
social impact