UO22+ uptake by proteins: Understanding the binding features of the super uranyl binding protein and design of a protein with higher affinity

Samuel O. Odoh, Gary D. Bondarevsky, Jason Karpus, Qiang Cui, Chuan He, Riccardo Spezia, Laura Gagliardi

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Abstract

The capture of uranyl, UO22+, by a recently engineered protein (Zhou et al. Nat. Chem. 2014, 6, 236) with high selectivity and femtomolar sensitivity has been examined by a combination of density functional theory, molecular dynamics, and free-energy simulations. It was found that UO22+ is coordinated to five carboxylate oxygen atoms from four amino acid residues of the super uranyl binding protein (SUP). A network of hydrogen bonds between the amino acid residues coordinated to UO22+ and residues in its second coordination sphere also affects the protein's uranyl binding affinity. Free-energy simulations show how UO22+ capture is governed by the nature of the amino acid residues in the binding site, the integrity and strength of the second-sphere hydrogen bond network, and the number of water molecules in the first coordination sphere. Alteration of any of these three factors through mutations generally results in a reduction of the binding free energy of UO22+ to the aqueous protein as well as of the difference between the binding free energies of UO22+ and other ions (Ca2+, Cu2+, Mg2+, and Zn2+), a proxy for the protein's selectivity over these ions. The results of our free-energy simulations confirmed the previously reported experimental results and allowed us to discover a mutant of SUP, specifically the GLU64ASP mutant, that not only binds UO22+ more strongly than SUP but that is also more selective for UO22+ over other ions. The predictions from the computations were confirmed experimentally.

Original languageEnglish (US)
Pages (from-to)17484-17494
Number of pages11
JournalJournal of the American Chemical Society
Volume136
Issue number50
DOIs
StatePublished - Dec 17 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

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