Journal Article

FZJ-2015-00150

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA

Musiani, F. (Corresponding Author) ; Rossetti, G.FZJ* ; Capece, L. ; Gerger, T. M. ; Micheletti, C. ; Varani, G. ; Carloni, P.FZJ*

2014
American Chemical Society Washington, DC

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Please use a persistent id in citations: doi:10.1021/ja507812v

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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. Computational Biomedicine (IAS-5)
3. Computational Biomedicine (INM-9)

Research Program(s):

1. 411 - Computational Science and Mathematical Methods (POF2-411) (POF2-411)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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