Abstract
The reduced derivative of α-conotoxin MI, a 14 amino acid peptide is characterized by NMR-pH titrations and molecular dynamics simulations to determine the protonation constants of the nine basic moieties, including four cysteine thiolates, and the charge-dependent structural properties. The peptide conformation at various protonation states was determined. The results show that the disulfide motifs in the native globular α-conotoxin MI occur between those cysteine moieties that exhibit the most similar thiolate basicities. Since the basicity of thiolates correlates to its redox potential, this phenomenon can be explained by the higher reactivity of the two thiolates with higher basicities. The folding of the oxidized peptide is further facilitated by the loop-like structure of the reduced form, which brings the thiolate groups into sufficient proximity. The 9 group-specific protonation constants and the related, charge-dependent, species-specific peptide structures are presented.
Highlights
The co-dependent thiolate-disulfide redox and thiolate-thiol acid-base equilibria are crucial components to maintain redox homeostasis and to form the solution structure of cysteine-containing peptides
While the native disulfide pattern in oxidized -conotoxin MI was determined by Gray et al.[9] to be uniform, it is known that these peptides can exhibit various disulfide patterns after reduction and guided oxidation under certain circumstances;[12] i. e., ribbon (C3– C14/C4 –C8) and bead (C3 –C4/C8 – C14) patterns besides the native globular pattern (C3 – C8/C4– C14)
Since the pH-dependent conformational changes often change the proximal environment of the basic moieties, as can be seen in the determined structures, it can be stated that the protonation constants of the basic moieties are different for each conformation of the peptide, great care must be used when discussing the acidbase character of the residues
Summary
The co-dependent thiolate-disulfide redox and thiolate-thiol acid-base equilibria are crucial components to maintain redox homeostasis and to form the solution structure of cysteine-containing peptides. These issues have recently attracted significant scientific interest.[1,2] While the related works mainly study molecules of one single thiol group and the concomitant heteronuclear disulfide formation,[3,4] no thorough analysis appeared on the parameters and mechanism of basicity-influenced multiple intramolecular disulfide formations, despite the fact that natural compounds of appropriate properties for such studies do exist, as follows. While the native disulfide pattern in oxidized -conotoxin MI was determined by Gray et al.[9] to be uniform, it is known that these peptides can exhibit various disulfide patterns after reduction and guided oxidation under certain circumstances;[12] i. e., ribbon (C3– C14/C4 –C8) and bead (C3 –C4/C8 – C14) patterns besides the native globular pattern (C3 – C8/C4– C14)
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