title: Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
abstract: The anti-AIDS drug rilpivirine undergoes conformational changes to bind HIV-1 reverse transcriptase (RT), which is an essential enzyme for the replication of HIV. These changes allow it to retain potency against mutations that otherwise would render the enzyme resistant. Here we report that water molecules play an essential role in this binding process. Femtosecond experiments and theory expose the molecular level dynamics of rilpivirine bound to HIV-1 RT. Two nitrile substituents, one on each arm of the drug, are used as vibrational probes of the structural dynamics within the binding pocket. Two-dimensional vibrational echo spectroscopy reveals that one nitrile group is unexpectedly hydrogen-bonded to a mobile water molecule, not identified in previous X-ray structures. Ultrafast nitrile-water dynamics are confirmed by simulations. A higher (1.51 Å) resolution X-ray structure also reveals a water-drug interaction network. Maintenance of a crucial anchoring hydrogen bond may help retain the potency of rilpivirine against pocket mutations despite the structural variations they cause.
authors: Ultrafast Optical Processes Laboratory, Department of Chemistry, University of Pennsylvania, Pennsylvania 19067, USA.
authors: Daniel G
authors: DG
authors: Kuroda
authors: Joseph D
authors: JD
authors: Bauman
authors: J Reddy
authors: JR
authors: Challa
authors: Disha
authors: D
authors: Patel
authors: Thomas
authors: T
authors: Troxler
authors: Kalyan
authors: K
authors: Das
authors: Eddy
authors: E
authors: Arnold
authors: Robin M
authors: RM
authors: Hochstrasser
mesh_terms: D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000068696:Rilpivirine; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D009570:Nitriles; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine