Spectroscopic studies of wild-type (WT) HIV-1 reverse transcriptase complex with inhibitor TMC278 (also known as rilpivirine and Edurant) in water have been extended to complexes of TMC278 with mutants Y181C/K103N and L100I/K103N. FTIR spectra demonstrated strong similarity of inhibitor binding in crystal and solution samples, and together with the 2D IR data revealed two transitions in the spectral region of the nitrile stretch vibration at 2215 and 2225 cm-1. Noticeable spectral broadening occurred for the weaker transition at 2225 cm-1 in the case of mutant/TMC278 complexes compared to WT/TMC278, suggesting increased solvent exposure. Classical MD simulations showed that the occurrence of H-bond formation at the nitrile end of the cinnamonitrile arm of TMC278 causes a blue shift and spectral broadening of the corresponding nitrile stretch frequency, confirming an increased solvent exposure of the binding pocket in accordance with recent high-resolution X-ray crystallography (1.5 � resolution structure of the complex).

Structure and dynamics of the non-nucleoside inhibitor TMC278/rilpivirine bound to HIV-1 reverse transcriptase

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.