No abstract

Polyamines are known to mediate diverse biological processes, and specifically to bind and stabilize compact conformations of nucleic acids, acting as chemical chaperones that promote folding by offsetting the repulsive negative charges of the phosphodiester backbone. However, whether and how polyamines modulate the structure and function of proteins remain unclear. In particular, early proteins are thought to have been highly acidic, like nucleic acids, due to a scarcity of basic amino acids in the prebiotic context. Perhaps polyamines, the abiotic synthesis of which is simple, could have served as chemical chaperones for such primordial proteins? We replaced all lysines of an ancestral 60-residue helix-bundle protein with glutamate, resulting in a disordered protein with 21 glutamates in total. Polyamines efficiently induce folding of this hyperacidic protein at submillimolar concentrations, and their potency scaled with the number of amine groups. Compared to cations, polyamines were several orders of magnitude more potent than Na + , while Mg 2+ and Ca 2+ had an effect similar to that of a diamine, inducing folding at approximately seawater concentrations. We propose that (i) polyamines and dications may have had a role in promoting folding of early proteins devoid of basic residues and (ii) coil−helix transitions could be the basis of polyamine regulation in contemporary proteins.

Systems chemistry has been a key component of origin of life research, invoking models of life’s inception based on evolving molecular networks. One such model is the graded autocatalysis replication domain (GARD) formalism embodied in a lipid world scenario, which offers rigorous computer simulation based on defined chemical kinetics equations. GARD suggests that the first pre-RNA life-like entities could have been homeostatically-growing assemblies of amphiphiles, undergoing compositional replication and mutations, as well as rudimentary selection and evolution. Recent progress in molecular dynamics has provided an experimental tool to study complex biological phenomena such as protein folding, ligand-receptor interactions, and micellar formation, growth, and fission. The detailed molecular definition of GARD and its inter-molecular catalytic interactions make it highly compatible with molecular dynamics analyses. We present a roadmap for simulating GARD’s kinetic and thermodynamic behavior using various molecular dynamics methodologies. We review different approaches for testing the validity of the GARD model by following micellar accretion and fission events and examining compositional changes over time. Near-future computational advances could provide empirical delineation for further system complexification, from simple compositional non-covalent assemblies towards more life-like protocellular entities with covalent chemistry that underlies metabolism and genetic encoding.

A recent breakthrough publication has reported complex organic molecules in the plumes emanating from the subglacial water ocean of Saturn's moon Enceladus (Postberg et al., 2018, Nature 558:564–568). Based on detailed chemical scrutiny, the authors invoke primordial or endogenously synthesized carbon-rich monomers (<200 u) and polymers (up to 8000 u). This appears to represent the first reported extraterrestrial organics-rich water body, a conceivable milieu for early steps in life's origin (“prebiotic soup”). One may ask which origin-of-life scenario appears more consistent with the reported molecular configurations on Enceladus. The observed monomeric organics are carbon-rich unsaturated molecules, vastly different from present-day metabolites, amino acids, and nucleotide bases, but quite chemically akin to simple lipids. The organic polymers are proposed to resemble terrestrial insoluble kerogens and humic substances, as well as refractory organic macromolecules found in carbonaceous chondritic meteorites. The authors posit that such polymers, upon long-term hydrous interactions, might break down to micelle-forming amphiphiles. In support of this, published detailed analyses of the Murchison chondrite are dominated by an immense diversity of likely amphiphilic monomers. Our specific quantitative model for compositionally reproducing lipid micelles is amphiphile-based and benefits from a pronounced organic diversity. It thus contrasts with other origin models, which require the presence of very specific building blocks and are expected to be hindered by excess of irrelevant compounds. Thus, the Enceladus finds support the possibility of a pre-RNA Lipid World scenario for life's origin.

Mixed lipid assemblies form dynamic aptamers that possess protein-like stereospecific recognition. This capacity can mediate assembly self-reproduction, supporting an early role for lipids in life's origin.

No abstract

Systems Chemistry has been a key component of origin of life research, invoking models of life&rsquo;s inception based on evolving molecular networks. One such model is the Graded Autocatalysis Replication Domain (GARD) formalism embodied in a Lipid World scenario, which offers rigorous computer simulation based on defined chemical kinetics equations. GARD suggests that the first pre-RNA life-like entities could have been homeostatically-growing assemblies of amphiphiles, undergoing compositional replication and mutations, as well as rudimentary selection and evolution. Recent progress in Molecular Dynamics has provided an experimental tool to study complex biological phenomena such as protein folding, ligand-receptor interactions and micellar formation, growth and fission. The detailed molecular definition of GARD and its inter-molecular catalytic interactions make it highly compatible with Molecular Dynamics analyses. We present a roadmap for simulating GARD&rsquo;s kinetic and thermodynamic behavior using various Molecular Dynamics methodologies. We review different approaches for testing the validity of the GARD model, by following micellar accretion and fission events and examining compositional changes over time. Near future computational advances could provide empirical delineation for further system complexification, from simple compositional non-covalent assemblies towards more life-like protocellular entities with covalent chemistry that underlies metabolism and genetic encoding.

Mixed lipid micelles were proposed to facilitate life through their documented growth dynamics and catalytic properties. Our previous research predicted that micellar self-reproduction involves catalyzed accretion of lipid molecules by the residing lipids, leading to compositional homeostasis. Here, we employ atomistic Molecular Dynamics simulations, beginning with 54 lipid monomers, tracking an entire course of micellar accretion. This was done to examine the self-assembly of variegated lipid clusters, allowing us to measure entry and exit rates of monomeric lipids into pre-micelles with different compositions and sizes. We observe considerable rate-modifications that depend on the assembly composition and scrutinize the underlying mechanisms as well as the energy contributions. Lastly, we describe the measured potential for compositional homeostasis in our simulated mixed micelles. This affirms the basis for micellar self-reproduction, with implications for the study of the origin of life.