This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Retroviruses such as HIV type 1 use a DNA polymerase enzyme known as reverse transcriptase, which enables the conversion of a single-stranded RNA into a double-stranded DNA, in a process that is essential for viral replication. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind in a hydrophobic binding pocket which is open only in the presence of the inhibitor molecule. TMC278 is one such NNRTI that binds in a hydrophobic binding pocket of HIV-1 RT between two beta shhets. The chemical structure of TMC278 is butterfly-like having a rigid pyrimidine linker with two torsionally flexible arms resembling cinnamonitrile (Ph-CH=CH-CN) and benzonitrile (Ph-CN), both of which are connected by NH groups to the central pyrimidine. Resistance to NNRTI treatment can arise from mutations in the residues in and around the binding pocket. Common mutations observed in NNRTI resistant variants include Tyr181Cys, Leu100Ile and Lys103Asn. Recent high-resolution XRD structures of TMC278 bound to the wild-type, K103N/Y181C and L100I/K103N variants of the HIV-1 RT show that the drug molecule is rigid and at the same time flexible enough to adapt to the structural changes in the binding pocket induced by the clinically relevant NNRTI resistant mutations. Recently we obtained high-resolution X-ray structure of the bound complex of HIV-1 RT with TMC278. In order to further investigate the binding properties of this complex we propose to use 2D IR techniques to study the motional freedom of the inhibitor molecule and the timescale of potential structural reorganization, using the localized CN vibrational modes of TMC278 as molecular probes of structure.
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