SAM (S‐adenosyl‐L‐Methionine) is the universal methyl donor used by cells, and is also the second most used cofactor after ATP. Methyltransferases catalyze the methylation of numerous biomolecules including DNA, protein, and RNA; and have a broad array of functions ranging from cell signaling to gene transcription. Abnormal levels of methyltransferases have been linked to malignant cellular states, cardiovascular diseases, and neurological diseases. Therefore, methyltransferases are an attractive drug target. Several inhibitors of histone PMTs (protein methyltransferases) have been used in the clinic, signifying PMTs as a target class. The SAM binding pocket in protein methyltransferases has been utilized by in drug design strategies. Yet, there is not high specificity when it comes to these drugs, making the drugs imperfect. Recent NMR work reveals that unbound SAM has high populations of different conformations in dynamic equilibrium, which means there may be multiple conformations when SAM is bound to methyltransferases. Having multiple conformations of SAM may allow for specific drugs to be designed to fit the unique pockets, allowing for higher drug specificity. Here we use vibrational spectroscopy, which is sensitive to molecular conformation and immune to timescale, to determine if these conformational dynamics persist when SAM is bound to PMTs. Molecular dynamic studies and small molecules studies support the hypothesis that various SAM conformations exist both when free and when bound to the proteins.
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