A multiscale free energy method reveals an unprecedented photoactivation of a bimetallic Os(II)-Pt(II) dual anticancer agent.

The photoreactivity of relatively large transition metal complexes is often limited to the description of the static potential energy surfaces of the involved electronic states. While useful to grasp some physical grounds of the photoinduced molecular responses, this approach does not statistically sample the multiple molecular degrees of freedom of the systems under investigation, which grow significantly if we consider the explicit coupling with the environment, and does not consider dynamic effects. The problem is even more complex if the reactivity takes place in the excited state. The present work uses state-of-the-art multiscale QM/MM dynamics to describe the photoactivation of a Pt(II)-unit of an in silico designed two-component Os(II)-Pt(II) assembly proposed for a dual anticancer approach, by explicitly accounting for both dynamic and environmental effects. We clearly identify a transition state region with partial metal-to-metal charge transfer ( 3 MMCT) character with no precedents in the scarce Ru(II)-Pt(II) analogues, indicative of a large synergistic effect between the Os(II) and Pt(II) metals and crucial in the photolabilization process of the Pt(II)-Cl bond. This is the first evidence of the ability of Os(II) to promote photoactivation of the Pt(II)-moiety, a contingency that would open new perspectives in this emerging field. The designed complex is therefore able to combine the traditional activity in photodynamic therapy (PDT) with the photoactivated chemotherapy (PCT) exerted by the Pt(II) unit, representing a new paradigm for a combined PDT/PCT anticancer approach while providing an advance in the methodology used to describe the photochemistry of transition-metal complexes in solution.