Stability of transient Cu+Aβ (1–16) species and influence of coordination and peptide configuration on superoxide formation

Drastic Effect of the Peptide Sequence on the Copper‐Binding Properties of Tripeptides and the Electrochemical Behaviour of Their Copper(II) Complexes

“…Furthermore, the calculations show that for this complex, the Cu II -to-Cu I reduction induces an important elongation of the CuÀOb ond length, from 2.05 to 3.52 (Figure 6a nd Figure S7, Supporting Information). [51] Calculations show that oxidation of the tricoordinated Cu I -AcHWH complex is not reversible, resulting in at ricoordinated Cu II species that is slightly less stable than the tetracoordinated one ( Figure 6). This is similar to that found for 3N1O Cu II -Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), for which molecular dynamics simulations indicated that CO decoordination occurs rapidly at t = 0.2 ps.…”

“…This is similar to that found for 3N1O Cu II -Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), for which molecular dynamics simulations indicated that CO decoordination occurs rapidly at t = 0.2 ps. [51] Calculations show that oxidation of the tricoordinated Cu I -AcHWH complex is not reversible, resulting in at ricoordinated Cu II species that is slightly less stable than the tetracoordinated one ( Figure 6). Such changes on thec oordination environment, however,d o not explain the significant difference (of~500 mV) observed between E pc and E pa ,s ince the computed oxidation and reduction potentiald iffer by less than 50 mV,w hich suggest that a coupled chemical reaction, such as amide protonation, should also be involved in the reduction process (Figure 8).…”

Towards High‐Throughput Modelling of Copper Reactivity Induced by Structural Disorder in Amyloid Peptides

“…The slight displacement of equatorial ligands,t ogether with the light push-and-pull movement of the axial water molecule, represents as mall reorganisationo ft he Cu site that hosts both oxidation states and the dioxygen electron shuttle. This flat energy pathway is an alternative to pathways that involved isplacemento fO (Asp1) from the Cu centre, [8,22] which involves ah igher reorganisation energy.T he data concerning DE 4 clearly showt hat the displacemento fl igands from the equatorial plane of Cu II -Ab is required to obtain Cu I -Ab by oxidising either ascorbate or superoxide. Indeed, the largest value of DE 4 in Figure 5( DE 4 = 30 kJ mol À1 ) is associatedw ith aC us ite having three ligands, with Nd(His6) anti to N(Asp1) and Ne(His13)b inding from the orthogonal direction, and thus represents T-like coordination of Cu I .T his coordination mode has been already addressed as ag ood candidate fore fficient Cu reduction.…”

“…In terms of truncated models, some of these configurations have been studied in the reduced state Cu I -Ab. [22] It is important to search for geometrical parameters, such as those reported in Ta bles 2a nd 3, that correlate with the sign of DE 2 ,a nd thus indicatew hether there is as pecific interaction that can favour or disfavour,f or instance, step 2i nt he proposed mechanism.I nterestingly,t he minimal distance between O 2 andC ui sn ot strongly correlated with the sign of the energy change DE 2 .F or instance, in set 1 there are five configurationsi nw hich the CuÀOd istance is longer than 3 ,b ut two of these configurations have DE 2 < À20 kJ mol À1 .T his shows that the charget ransfer is energeticallyf avoured even at CuÀOd istances for which aC u ÀOc ovalentb ond is absent.…”

“…In terms of number of probed structures, this work extends similarw orks reportedi nt he literature tackling the same problem. [22] ReactionM echanism According to recente xperimental results, [1] the first step in ROS production catalysed by Cu-Ab is the in situ production of superoxide. The latter rapidlya ttacks other sites in the peptide and in its environment.…”