Novel Covalent Bond in Proteins: Calculations on Model Systems Question the Bond Stability

Abstract

We have investigated the sulfilimine covalent link between methionine (Met) and lysine (Lys), recently identified in collagen IV (R. Vanacore, A.-J. L. Ham, M. Voehler, C. R. Sanders, T. P. Conrads, T. D. Veenstra, K. B. Sharpless, P. E. Dawson, B. G. Hudson, Science 2009, 325, 1230), and have explored its stability with respect to both the redox processes and UV radiation by means of advanced computational methods. We have concluded that the bond should be present in a protonated state, (-NH=S-)(+). The bond is characterized by a relatively high standard reduction potential, that is, the bond should not be stable in a typical cell environment; if the sulfilimine bond exists (as suggested by the experiment) then the bond has to be supported by the protein environment. The sulfilimine bond then destabilizes the protein structure with respect to the alternative tertiary structure. We discuss conditions under which the bond could be formed as well as other possible structural arrangements consistent with the Met-Lys stoichiometry; some of the alternative bond motifs are more thermodynamically stable than the sulfilimine bond. We suggest that the character of the Met-Lys contact could be approached via NEXAFS spectroscopy. Finally, we show that the protonation brings photostability to the sulfilimine bond.

Computational insights into the formation and nature of the sulfilimine bond in collagen-IV

“…Meanwhile, the proton affinity of the nitrogen centre in the single protonated sullimine bonded species is calculated to be slightly lower than that of water at 975.0 kJ mol À1 . Thus, the present results indicate that under expected biological conditions the sullimine crosslink is most likely single protonated, in agreement with a previous computational study, 21 but has the potential to vary its protonation state; but it is unlikely neutral.…”

“…20 Meanwhile, another computational study concluded that the sullimine bond is protonated at pH 7. 21 In this present study we have applied computational chemistry methods to examine the proposed mechanisms by which the sullimine bond formation in collagen IV is mediated by the hypohalous acids HOX (X ¼ Cl and Br). More specically, using molecular dynamics (MD) simulations, quantum mechanical (QM)-cluster methods to examine possible mechanisms for formation of possible sullimine crosslinks.…”

“… 20 Meanwhile, another computational study concluded that the sulfilimine bond is protonated at pH 7. 21 …”

Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV

“…Previous computational studies 26 have suggested that such a bond is in fact better described as a coordinate covalent, or dative, bond. A previous computational study 27 and, more recently, our own computational studies 28 suggest that such bonds are not neutral within a biological context but instead are most likely protonated and furthermore, that this modifies the properties of the bond. It is in fact noted that protonation is one of the most important biochemical processes, especially to stabilize protein structure or biological cross-links.…”

Sulfilimine bond formation in collagen IV

“…In 2011, Ončák et al 47 conducted a computational study aimed at examining the stability of the sulfilimine bond and determining whether the sulfilimine crosslink is in a neutral or protonated state. They specifically focused on the protonation states of the sulfilimine crosslink, considering that the second amino group of lysine remains charged.…”