Zn protein simulations including charge transfer and local polarization effects.

Nearly half of all proteins contain metal ions, which perform a wide variety of specific functions associated with life processes. However, insights into the local/global, structural and dynamical fluctuations in metalloproteins from molecular dynamics simulations have been hampered by the "conventional" potential energy function (PEF) used in nonmetalloprotein simulations, which does not take into the nonnegligible charge transfer and polarization effects in many metal complexes. Here, we have carried out molecular dynamics simulations of Zn(2+) bound to Cys(-) and/or His(0) in proteins using both the conventional PEF and a novel PEF that accounts for the significant charge transfer and polarization effects in these Zn complexes. Simulations with the conventional PEF yield a nontetrahedral Cys(2)His(2) Zn-binding site and significantly overestimate the experimental Zn-S(Cys(-)) distance. In contrast, simulations with the new PEF accurately reproduce the experimentally observed tetrahedral structures of Cys(2)His(2) and Cys(4) Zn-binding sites in proteins, even when the simulation started from a nontetrahedral Zn(2+) configuration. This suggests that simulations with the new PEF could account for coordinational changes at Zn, which occurs during the folding/unfolding of Zn-finger proteins and certain enzymatic reactions The strategy introduced here can easily be applied to investigate Zn(2+) interacting with protein ligands other than Cys(-) and His(0). It can also be extended to study the interaction of other metals that have significant charge transfer and polarization effects.