Two-dimensional infrared spectra reveal relaxation of the nonnucleoside inhibitor TMC278 complexed with HIV-1 reverse transcriptase

Chong Fang, Joseph D. Bauman, Kalyan Das, Amanda Remorino, Eddy Arnold, Robin M. Hochstrasser

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

The two nitrile groups at the wings of the nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor TMC278 are both identified in high-sensitivity 2D IR spectroscopy experiments of the HIV-1 RT/TMC278 complex. The vibrational spectra indicate that the two arms of the inhibitor sense quite different environments within the hydrophobic pocket. The vibrational relaxation of the two arms are almost equal at 3 ps from model studies. The 2D IR spectra expose a significant distribution of nitrile frequencies that diffuse at equilibrium on ultrafast time scales ranging from hundreds of femtoseconds to tens of picoseconds. The slow spectral diffusion of the cyanovinyl arm of the inhibitor is attributed to its interaction with the backbone and side chains in the hydrophobic tunnel. The results show that the inhibitor cyano modes lose memory of their structural configurations relative to the hydrophobic pocket within tens of picoseconds. The cross-peaks between the two arms of the drug are tentatively attributed to relaxation of the nitrile state with both arms excited.

Original languageEnglish (US)
Pages (from-to)1472-1477
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number5
DOIs
StatePublished - Feb 5 2008

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • 2D IR spectroscopy
  • Ultrafast protein response
  • Vibrational relaxation

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