The project aims to identify biologically significant non-histone targets of clinically relevant and evolutionary conserved lysine methyltransferases (KMTs), and to further explore their structural-functional-dynamical relationships. Currently, there is limited understanding of how KMTs modulate non-histone proteins. To address this, the project will utilize experimentally identified candidate substrates from nuclear extracts and further implement extensive computational chemistry methods to identify true candidates. Beyond identifying true candidates, the work aims to identify the specific methylated sites on the non-histone proteins. Also, a detailed study will be implemented to identify key structural determinants governing KMTs substrate specificity, followed by experimental validation confirming methylated non-histones. Subsequently, the discovered substrate could serve as entry point of rational inhibitor design utilizing structure-based drug design and peptidomimetics targeting the protein-protein interface. Thus, the overall objective is to leverage synergy of computational chemistry and molecular genetics to fill the scientific gap in the field of epigenetic regulation.