Reactivity of Alanylalanine Diastereoisomers in Neutral and Acid Aqueous Solutions: a Versatile Stereoselectivity

Abstract

A good comprehension of the reactivity of peptides in aqueous solution is fundamental in prebiotic chemistry, namely for understanding their stability and behavior in primitive oceans. Relying on the stereoselectivity of the involved reactions, there is a huge interest in amino acid derivatives for explaining the spontaneous emergence of homochirality on primitive Earth. The corresponding kinetic and thermodynamic parameters are however still poorly known in the literature. We studied the reactivity of alanylalanine in acidic to neutral conditions as a model system. The hydrolysis into amino acids, the epimerization of the N-terminal residue, and the cyclization into diketopiperazine could be successfully identified and studied. This kinetic investigation highlighted interesting behaviors. Complex mechanisms were observed in very acidic conditions. The relative kinetic stability of the diastereoisomers of the dipeptide is highly dependent of the pH, with the possibility to dynamically destabilize the thermodynamically more stable diastereoisomers. The existence of the cyclization of dipeptides adds complexity to the system. On one hand it brings additional stereoselectivities; on the other hand fast racemization of heterochiral dipeptides is obtained.

Pathways for the formation and evolution of peptides in prebiotic environments

“…119 This was experimentally confirmed, showing additionally that heterochiral dipeptides are more stable in neutral pH, 71 while the thermodynamic equilibrium shifts back in favour of homochiral dipeptides under acid conditions. 72 As for the kinetics of depolymerization, a faster hydrolysis of homochiral dipeptides was indeed observed, except under very acidic conditions. These results tend to indicate that the stereoselectivities under weakly acidic conditions are at least qualitatively consistent with the APED model.…”

“…[69][70][71] It is worth noting that the prevailing formation of cycles with residues of identical configurations has been reported when DKP is formed by reacting the free dipeptide (Ala) 2 in hot water at neutral pH. 72 Once formed, DKPs undergo hydrolysis rapidly, which depending on residues can lead to the original dipeptide or to an inversion of sequence. Furthermore, it has been shown that DKPs epimerize faster than the corresponding peptides, 73 and have thus been considered as the main pathway of peptide epimerization.…”

The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

“…In addition to non-favourable polymerization thermodynamics, the course of peptide elongation is hindered by side-reactions such as the formation of diketopiperazines (DKP) inducing a termination at the dipeptide stage (Brack et al 1976;Rode 1999;Kawamura et al 2009). However, diketopiperazines have also been proposed as intermediates of peptide polymerization at high temperature (Nagayama et al 1990;Takaoka et al 1991;Lambert 2008;Kawamura et al 2005;Cleaves et al 2009;Plasson et al 2011), though, at least in part in this case, the length of peptides formed would be limited by thermodynamics. Additionally, the major pathway of cleavage of peptides occurs through cyclisation at the N-terminus yielding diketopiperazines (Steinberg and Bada 1983;Bujdak and Rode 2004;Danger et al 2010).…”

Chiral and chemical oscillations in a simple dimerization model

“…In particular, β and γ can also be chosen to unity, i.e., depolymerization and epimerization need not be stereoselective in order to produce oscillations, although heterodimers must be polymerized preferentially. Recent experimental results demonstrate the stereoselectivity of polymerization reactions and show in detail that the stereoselectivities can be modified experimentally (e.g., by pH) in magnitude and can be found to be both larger or smaller than unity 18,19 .…”