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Determinants of the Lead(II) Affinity in pbrR Protein: A Computational Study
journal contribution
posted on 2019-12-12, 18:47 authored by Iogann Tolbatov, Nazzareno Re, Cecilia Coletti, Alessandro MarroneInvestigation of the diverse evolutionary developed mechanisms
enabling bacteria to maintain homeostasis and to be resistant to lead
is crucial for the discovery of novel strategies for isolation of
this highly toxic metal and its subsequent elimination from contaminated
environments. The metalloregulatory protein pbrR and
its homologues that were identified in the Cupriavidus metallidurans
CH34 chromosome are the only characterized natural metalloproteins
that have a special affinity toward Pb(II) and that bind it with at
least a 1000-fold selectivity over other heavy metals. The X-ray structures
of apo and Pb(II)-bound pbrR have been recently reported.
In the present study, the binding of Pb(II) at pbrR was investigated by means of multiscale computational modeling.
Molecular dynamics simulations substantiated how conformations amenable
for the Pb(II) complexation through the tris-cysteine motif are formed
from the antiparallel coiled-coil packing interaction of two dimerization
helices of two pbrR monomers, and the phase space
of apo-pbrR has been extensively sampled. Hybrid
quantum mechanics/molecular mechanics (QM/MM) calculations on metal-bound
structures of pbrR also allowed us to determine the
most probable protonation state for the lead binding motif and evaluate
the structural features mostly affecting the Pb(II) coordination in
this protein. In agreement with available experimental data, we found
that pbrR may control its Pb(II) affinity, probably,
by conformational changes that affect the distance between Cys78′
and Cys122 and their protonation states, thus being able to switch
on the Pb(II) sequestration/release-prone states in response to external
stimuli. The protein structure enveloping the metal binding motif
favors the thiol–thiolate-thiolate protonation state of Pb(II)-pbrR, thus probably enhancing the binding selectivity for
Pb(II), compared to other metal ions.
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Keywords
metalloregulatory protein pbrRpbrR monomersbinding motifMolecular dynamics simulationsmetal ionsX-ray structuresbinding selectivityprotonation statesPbantiparallel coiled-coildimerization helicesmetal binding motifComputational Study Investigationprotein structureCys 122tris-cysteine motifmetal-bound structuresphase spacepbrR Proteinnovel strategiesCupriavidus metallidurans CH 34 chromosomeprotonation stateQM
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