Energetic processes driving potential peptide protometabolisms at the origin of living systems – PeptiSystems

The PeptiSystems project aims at combining the physicochemical analysis of the conditions of the origins of life, with an experimental approach. This analysis is centered on the idea that a free energy income to a chemical system is necessary to maintain it far enough from equilibrium so that non linear processes take over a direct evolution toward equilibrium, and become autonomous.
The theoretical developments will constitute the starting point of experimental studies of this project and a matter of ongoing investigations to contribute to a better understanding of the physico-chemical origin of complexity. Within this perspective, the emergence of protometabolisms, defined as networks of chemical reactions proceeding under far-from-equilibrium conditions and involving nonlinear features therefore being capable of generating self-organisation (associated with a local decrease in entropy compensated by the irreversibility of the overall process), is a key step for the origin of life.
This programme involves the experimental study of the chemical reactivity of energy-rich amino acids derivatives, in dilute aqueous solution and in the presence of activating agents (chemical, photochemical) and/or catalysts, to characterise these activation pathways. To this purpose, we implement classical tools of organic and analytical chemistry (NMR, HPLC, GC-MS…), while focusing on e.g. systems that would allow the conversion of light energy into chemical energy. We are also investigating the chemical interactions between amino acid and nucleoitide derivatives.

The latest developments on theoretical fundations have put a stress both on the importance of dynamic kinetic stability, and on the importance of the energetic cost of irreversibility in self-organisation processes. This leads to requalify the criteria of habitability in the scope of the emergence of life (higher constraints than for habitability as suitability to the persistence of extant life); underthe light of these revised criteria, hydrothermal (e.g. submarine) environments or icy planetary bodies appear as unlikely to host some emergence of life.
A comparative experimental study of various activating agents showed that those having a 'high potential' better favour self-organisation processes, while agents having a 'low potential' lead to evolutionary dead ends in a prebiotic context.
An experimental research on the activation of peptides by UV irradiation was carried out in detail, however without affording all expected results – what illustrates the complexity of the problem to be solved.
The interaction between amino acid- and nucleotide derivatives shows original, interesting reactivity features (including that of phosphate esters), the latter constituting simple models of elementary acts of biochemical processes involved in the translation of RNA into proteins.
These works are published or will soon be submitted.

The identification of photochemical conversion systems is a difficult approach that requires substantial work. The investigation of activating systems is going on with testing a larger palette of energy rich chemical compounds, together with a critic reassessment of associated literature data.
Recent results obtained in the scope of peptide/nucleotide interactions might be of high importance for the emergence of the biochemical translation process. Progress on this topic motivates the consolidation of our international collaborations with top- rank researchers.
Our international collaboration on theoretical fundations lead to a deepening of our vision centered on the idea of persoistence, which allows to perceive a conceptual unification of the two main XIXth century theories accounting for change: the Second Law of theromdynamic, ant the evolution theory proposed by Charles Darwin. A perspective article published on end 2015 in Chemical Communications, develops this idea of a persoistence principle of purely logical kind (a spontaneous change can only lead to more persistent states, and in fine to a system that does not change anymore), that would englobe both evolutionary dynamics, the one based on the maximisation of probability (the Second Law) and the other based on exponential growth of (self-replicating) populations.
This understanding of the driving forces governing evolution is proper to facilitate the research of chemical systems able to sustain it, and motivates the development of the PeptiSystems project, and more generally could contribute to remove the conceptual barrier that separates physical sciences from life sciences.

• 6 research articles:
R. Pascal, Isr J Chem 2015, 55, 865–874. DOI: 10.1002/ijch.201400193
R. Pascal, A. Pross, Chem Communi 2015, 51(90), 16160–16165. DOI: 10.1039/C5CC06260H
D. Beaufils, S. Jepaul, Z. Liu, L. Boiteau, R. Pascal, Orig Life Evol Biosph 2016, 46(1), 19–30. DOI: 10.1007/s11084-015-9455-0
S. Murillo Sánchez, D. Beaufils, J. M. González Mañas, R. Pascal, K. Ruiz-Mirazo, Chem Sci 2016, 7(5), 3406–3413. DOI: 10.1039/c5sc04796j
R. Pascal, Astrobiology 2016, 16, 328–334. DOI: 10.1089/ast.2015.1412
R. Pascal, A. Pross, Orig Life Evol Biosph 2016, DOI: 10.1007/s11084-016-9494-1
• 15 oral presentations in conferences and workshops (incl. 7 international invited lectures)
• 1 outreach article:
R. Pascal, G. Danger, L’Actualité Chimique 2015, 393–394, 17–23.
• Several outreach lectures and actions.

The ongoing detection of numerous exoplanets with conditions becoming more and more similar to that of the Earth places the question of the plurality of living worlds at the forefront of unresolved scientific issues. However, studies on the possible nature and emergence of other forms of life, as well as their detection can only be undertaken in an interdisciplinary way. Life on Earth constitutes a historical process that developed by complexification starting from chemical systems. It is considered in this project that both physico-chemical driving forces and contingency are responsible for this process since its early beginning, which means that non-historical aspects deserve a scientific approach, which is of general interest in astrobiology. The theoretical developments will constitute the starting point of experimental studies of this project and a matter of ongoing investigations to contribute to a better understanding of the physico-chemical origin of complexity. Within this perspective, the emergence of protometabolisms defined as networks of chemical reactions proceeding under far from equilibrium conditions and involving nonlinear features and therefore being capable of generating self-organisation (associated with a local decrease in entropy compensated by the irreversibility of the overall process) is a key step for the origin of life. Chemical networks of this kind must work as unidirectional (kinetically irreversible) sequences of reactions or preferably as unidirectional reaction cycles in which a further process of positive chemical feedback would be capable of generating systems endowed with autocatalytic properties and then behaving in a nonlinear way. Determining which pathways could have constantly or repeatedly fed these systems with energy to maintain the far from equilibrium state is then essential to understand how self-organisation could emerge. This approach is applied to the formation of biopolymers capable of functional activities that is generally considered as a prerequisite for the development of life. Our original goal is to propose an overall scenario integrating the formation of peptides and other related processes to build a network capable of giving rise to emergent properties related to the connections of the different parts of the network. The project is aimed (i) at understanding how peptides could be formed under prebiotic conditions and how energy sources could have been coupled to peptide bond formation. But it is not limited to this goal since peptides made from racemic mixtures of amino acids are unlikely to adopt definite structures needed for specific activity so that it will address (ii) the question of the emergence of selectivity (stereoselectivity and sequences with single handedness or defined structure) or that of improbable but dynamically stable states. Lastly, the emergence of translation at an early stage of evolution suggests that the chemistry of amino acids and peptides can be coupled to that of an information carrier supporting the hypothesis of a peptide-nucleotide co-evolution. (iii) Developing knowledge about chemical pathways through which amino acids or short peptides could have interacted with ribonucleotides monomers and oligomers is a prerequisite for understanding the emergence of the translation process and will constitute a priority in our investigations. All these topics will be experimentally investigated by monitoring the reactions through common methods of analytical chemistry and organic chemistry (NMR, HPLC, MS, UV…).