Development of a New AMBER Force Field for Cysteine and Histidine Cadmium‐Binding Proteins and Its Validation Through QM/MM MD Simulations

We developed and validated a novel force field in the context of the AMBER parameterization for the simulation of cadmium(II)-binding proteins. The proposed force field takes into account the polarization effect produced by the central ion on its surroundings. The new polarized atomic charges for cysteine and histidine residues were derived based on the available structures of cadmium-bearing proteins using QM calculations and QM/MM simulations. The developed force field was validated by performing molecular dynamics simulations on several cadmium(II)-binding proteins. Our model preserves the tetra-coordination of the metal site with remarkable stability, yielding mean distances between <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:mrow><mml:msup><mml:mi>Cd</mml:mi> <mml:mrow><mml:mn>2</mml:mn> <mml:mo>+</mml:mo></mml:mrow> </mml:msup> </mml:mrow> <mml:annotation>$$ {\mathrm{Cd}}^{2+} $$</mml:annotation></mml:semantics> </mml:math> ion and S or N atoms of the binding residues in close agreement with experimental data.