From simple to complex: multiscale modeling of metal-mediated protein interactions to uncover mechanistic insights into the action of inorganic drugs

This Perspective article explores the crucial role of computational and experimental models in protein metalation studies which is at the heart of advancing inorganic medicinal drugs. The intricate world of protein-inorganic drug interactions poses a significant challenge to computational and experimental characterisation. Indeed, the vast conformational landscapes and dynamic behaviours of proteins demand sophisticated modelling strategies to accurately predict drug behaviour and mechanism of action. Using selected examples, this article demonstrates how research progresses from simple models to increasingly complex systems, thereby facilitating the acquisition of comprehensive mechanistic insights. An effective and pragmatic strategy for navigating this complexity is to deliberately use simple models as steppingstones towards understanding more intricate protein metalation phenomena. This hierarchical modelling paradigm enables researchers to systematically develop an understanding of processes ranging from fundamental atomic interactions to the entire protein-drug dynamic, balancing computational and experimental feasibility with deep mechanistic insight.