Parameterization\nof a Fluctuating Charge Model for\nComplexes Containing 3d Transition Metals

Metalloproteins widely exist in biology,\nplaying pivotal\nroles\nin diverse life processes. Meanwhile, molecular dynamics (MD) simulations\nbased on classical force fields has emerged as an important tool in\nscientific research. Partial charges are critical parameters within\nclassical force fields and usually derived from quantum mechanical\n(QM) calculations. However, QM calculations are often time-consuming\nand prone to basis set dependence. Alternatively, fluctuating charge\n(FQ) models offer another avenue for partial charge derivation, which\nhas significant speed advantages and can be used for large-scale\nscreening. Building upon our previous work, which introduced an FQ\nmodel for zinc-containing complexes, herein we extend this model to\ninclude additional 3d transition metals which are important to the\nlife sciences, namely chromium, manganese, iron, cobalt, and nickel.\nEmploying CM5 charges as target for parametrization, our FQ model\naccurately reproduces partial charges for 3d metal complexes featuring\nbiologically relevant ligands. Furthermore, by using atomic charges\nderived by our FQ model, MD simulations have been performed. These\ncharges showed excellent performance in simulating proteomic metal\nsites housing multiple metal ions, specifically, a metalloprotein\ncontaining an iron–sulfur cluster and another containing a\ndimanganese metal site, showcasing comparable performance to those\nof RESP charges. We anticipate that our study can accelerate the parametrization\nof atomic charges for metalloproteins featuring 3d transition metals,\nthereby facilitating simulations of relevant systems.