Abstract
The octarepeat region of the prion protein can bind Cu2+ ions up to full occupancy (one ion per octarepeat) at neutral pH. While crystallographic data show that the HGGG octarepeat subdomain is the basic binding unit, multiple histidine coordination at lower Cu occupancy has been reported by X-ray absorption spectroscopy, EPR, and potentiometric experiments. In this paper we investigate, with first principles Car–Parrinello simulations, the first step for the formation of the Cu low-level binding mode, where four histidine side chains are coordinated to the same Cu2+ ion. This step involves the further binding of a second histidine to an already HGGG domain bonded Cu2+ ion. The influence of the pH on the ability of Cu to bind two histidine side chains was taken into account by simulating different protonation states of the amide N atoms of the two glycines lying nearest to the first histidine. Multiple histidine coordination is also seen to occur when glycine deprotonation occurs and the presence of the extra histidine stabilizes the Cu–peptide complex. Though the stabilization effect slightly decreases with the number of deprotonated glycines (reaching a minimum when both N atoms of the two nearest glycines are available as Cu ligands), the system is still capable of binding the second histidine in a 4N tetrahedral (though slightly distorted) coordination, whose energy is very near to that of the crystallographic square-planar 3N1O coordination. This result suggests that at low metal concentration the reorganization energy associated with Cu(II)/Cu(I) reduction is small also at pH ~ 7, when glycines are deprotonated.
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Notes
Actually the Makov–Payne correction also applies to systems with a nonvanishing dipole moment, irrespective of their charge. For the systems of interest here, this bit of the correction is, however, very small.
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Acknowledgments
We thank P. Giannozzi and C. Cavazzoni for invaluable suggestions and constant help. The computations were performed on Linux clusters at the E. Fermi Research Center (Rome, Italy), at the BEN facility of the ECT* Institute (Trento, Italy), at Cineca (Bologna, Italy), and on locally assembled hardware. Financial support from Firb 2003 projects RBNE03PX83, PRIN05, and PRIN06 is acknowledged.
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Guerrieri, F., Minicozzi, V., Morante, S. et al. Modeling the interplay of glycine protonation and multiple histidine binding of copper in the prion protein octarepeat subdomains. J Biol Inorg Chem 14, 361–374 (2009). https://doi.org/10.1007/s00775-008-0454-8
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DOI: https://doi.org/10.1007/s00775-008-0454-8