Screening has been able to identify a number of potentially interesting molecules that bind to Staurosporine quadruplex DNAs. Efficient methods for obtaining structural information on the complexes are needed for critical evaluation of the candidate molecules. An enhanced hydroxyl radical cleavage protocol can provide nucleotide resolution structural information about the using complexes of drug like molecules. This approach is demonstrated here with the chair type quadruplex structure formed by the 15 mer d that is often referred to as the thrombin binding aptamer, TBA. An overview of the protocol is depicted in Figure 1. The extent of hydroxyl radical cleavage at a particular residue is proportional to the solvent accessibility of the sugar of that residue. Formation of a complex can also lead to enhanced cleavage by altering the structure such that the sugar is more exposed to hydroxyl radical. The hydroxyl radical is a neutral molecule and this is an important feature as many quadruplex DNAs have large electrostatic potentials. It is noted that this approach also has the potential to gain new information about the folding patterns of quadruplex DNAs. The crystal structure of the R428 ribosome was used to validate the application of the hydroxyl radical cleavage approach to the monitoring of complex nucleic acid folding patterns and interactions. The changes in extent of cleavage due to drug like molecule binding can indicate which residues of the DNA are spatially close to one another as depicted in Figure 1. This approach could also be applied to the quadruplex aptamers used in sensors. The drug like molecules used here include NMM and TmPyP4 that have been previously identified as quadruplex binders. NSC 176319, Cain��s quinolinium was found using the screening method previously described. NSC 91881 was identified in a structurally similarity search to NSC 176319 and then screened. The results of the hydroxyl radical approach have been validated and extended by the application of NMR methods to the complexes. The quadruplex DNAs of interest are typically much smaller than most of the DNA and RNA that have been investigated by hydroxyl radical cleavage reactions. One of the challenges with the use of a small DNA is the purification of the even smaller fragments from the reagents that are used to generate and to quench the hydroxyl radicals.