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Combined EXAFS and DFT Structure Calculations Provide Structural Insights into the 1:1 Multi‐Histidine Complexes of Cu II , Cu I , and Zn II with the Tandem Octarepeats of the Mammalian Prion Protein
Author(s) -
Pushie M. Jake,
Nienaber Kurt H.,
McDonald Alex,
Millhauser Glenn L.,
George Graham N.
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201304201
Subject(s) - extended x ray absorption fine structure , chemistry , crystallography , density functional theory , x ray absorption spectroscopy , coordination number , coordination complex , spectroscopy , metal , coordination sphere , absorption spectroscopy , histidine , copper , absorption (acoustics) , computational chemistry , materials science , ion , crystal structure , physics , amino acid , organic chemistry , quantum mechanics , composite material , biochemistry
The metal‐coordinating properties of the prion protein (PrP) have been the subject of intense focus and debate since the first reports of its interaction with copper just before the turn of the century. The picture of metal coordination to PrP has been improved and refined over the past decade, but structural details of the various metal coordination modes have not been fully elucidated in some cases. In the present study, we have employed X‐ray absorption near‐edge spectroscopy as well as extended X‐ray absorption fine structure (EXAFS) spectroscopy to structurally characterize the dominant 1:1 coordination modes for Cu II , Cu I , and Zn II with an N‐terminal fragment of PrP. The PrP fragment corresponds to four tandem repeats representative of the mammalian octarepeat domain, designated as OR 4 , which is also the most studied PrP fragment for metal interactions, making our findings applicable to a large body of previous work. Density functional theory (DFT) calculations have provided additional structural and thermodynamic data, and candidate structures have been used to inform EXAFS data analysis. The optimized geometries from DFT calculations have been used to identify potential coordination complexes for multi‐histidine coordination of Cu II , Cu I , and Zn II in an aqueous medium, modelled using 4‐methylimidazole to represent the histidine side chain. Through a combination of in silico coordination chemistry as well as rigorous EXAFS curve‐fitting, using full multiple scattering on candidate structures derived from DFT calculations, we have characterized the predominant coordination modes for the 1:1 complexes of Cu II , Cu I , and Zn II with the OR 4 peptide at pH 7.4 at atomic resolution, which are best represented as square‐planar [Cu II (His) 4 ] 2+ , digonal [Cu I (His) 2 ] + , and tetrahedral [Zn II (His) 3 (OH 2 )] 2+ , respectively.