Preferential attachment renders an evolving network of populations robust against crashes

We study a model for the evolution of chemical species under a combination of population dynamics on a short time scale and a selection mechanism on a longer time scale. Least fit nodes are replaced by new nodes whose links are attached to the nodes of the given network via preferential attachment. In contrast to a random attachment of newly incoming nodes that was used in previous work, this preferential attachment mechanism accelerates the generation of a so-called autocatalytic set after a start from a random geometry and the growth of this structure until it saturates in a stationary phase in which the whole system is an autocatalytic set. Moreover, the system in the stationary phase becomes much more stable against crashes in the population size as compared to random attachment. We explain in detail in terms of graph theoretical notions which structure of the resulting network is responsible for this stability. Essentially it is a very dense core with many loops and less nodes playing the role of a keystone that prevents the system against crashes almost completely.Comment: 12 pages, 9 figures, 2 table

On the Free Energy That Drove Primordial Anabolism

A key problem in understanding the origin of life is to explain the mechanism(s) that led to the spontaneous assembly of molecular building blocks that ultimately resulted in the appearance of macromolecular structures as they are known in modern biochemistry today. An indispensable thermodynamic prerequisite for such a primordial anabolism is the mechanistic coupling to processes that supplied the free energy required. Here I review different sources of free energy and discuss the potential of each form having been involved in the very first anabolic reactions that were fundamental to increase molecular complexity and thus were essential for life

Bio-inspired CO₂ conversion by iron sulfide catalysts under sustainable conditions

The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents

Energetic Selection of Topology in Ferredoxins

Models of early protein evolution posit the existence of short peptides that bound metals and ions and served as transporters, membranes or catalysts. The Cys-X-X-Cys-X-X-Cys heptapeptide located within bacterial ferredoxins, enclosing an Fe4S4 metal center, is an attractive candidate for such an early peptide. Ferredoxins are ancient proteins and the simple α+β fold is found alone or as a domain in larger proteins throughout all three kingdoms of life. Previous analyses of the heptapeptide conformation in experimentally determined ferredoxin structures revealed a pervasive right-handed topology, despite the fact that the Fe4S4 cluster is achiral. Conformational enumeration of a model CGGCGGC heptapeptide bound to a cubane iron-sulfur cluster indicates both left-handed and right-handed folds could exist and have comparable stabilities. However, only the natural ferredoxin topology provides a significant network of backbone-to-cluster hydrogen bonds that would stabilize the metal-peptide complex. The optimal peptide configuration (alternating αL,αR) is that of an α-sheet, providing an additional mechanism where oligomerization could stabilize the peptide and facilitate iron-sulfur cluster binding

Emergence of light-driven protometabolism on recruitment of a photocatalytic cofactor by a self-replicator

Establishing how life can emerge from inanimate matter is among the grand challenges of contemporary science. Chemical systems that capture life’s essential characteristics—replication, metabolism and compartmentalization—offer a route to understanding this momentous process. The synthesis of life, whether based on canonical biomolecules or fully synthetic molecules, requires the functional integration of these three characteristics. Here we show how a system of fully synthetic self-replicating molecules, on recruiting a cofactor, acquires the ability to transform thiols in its environment into disulfide precursors from which the molecules can replicate. The binding of replicator and cofactor enhances the activity of the latter in oxidizing thiols into disulfides through photoredox catalysis and thereby accelerates replication by increasing the availability of the disulfide precursors. This positive feedback marks the emergence of light-driven protometabolism in a system that bears no resemblance to canonical biochemistry and constitutes a major step towards the highly challenging aim of creating a new and completely synthetic form of life. [Figure not available: see fulltext.]

Fe(ii) and Fe(iii) dithiocarbamate complexes as single source precursors to nanoscale iron sulfides: a combined synthetic and in situ XAS approach

Nanoparticulate iron sulfides have many potential applications and are also proposed to be prebiotic catalysts for the reduction of CO2 to biologically important molecules, thus the development of reliable routes to specific phases with controlled sizes and morphologies is important. Here we focus on the use of iron dithiocarbamate complexes as single source precursors (SSPs) to generate greigite and pyrrhotite nanoparticles. Since these minerals contain both iron(III) and iron(II) centres, SSPs in both oxidation states, [Fe(S2CNR2)3] and cis-[Fe(CO)2(S2CNR2)2] respectively, have been utilised. Use of this Fe(II) precursor is novel and it readily loses both carbonyls in a single step (as shown by TGA measurements) providing an in situ source of the extremely air-sensitive Fe(II) dithiocarbamate complexes [Fe(S2CNR2)2]. Decomposition of [Fe(S2CNR2)3] alone in oleylamine affords primarily pyrrhotite, although by careful control of reaction conditions (ca. 230 °C, 40–50 nM SSP) a window exists in which pure greigite nanoparticles can be isolated. With cis-[Fe(CO)2(S2CNR2)2] we were unable to produce pure greigite, with pyrrhotite formation dominating, a similar situation being found with mixtures of Fe(II) and Fe(III) precursors. In situ X-ray absorption spectroscopy (XAS) studies showed that heating [Fe(S2CNiBu2)3] in oleylamine resulted in amine coordination and, at ca. 60 °C, reduction of Fe(III) to Fe(II) with (proposed) elimination of thiuram disulfide (S2CNR2)2. We thus carried out a series of decomposition studies with added thiuram disulfide (R = iBu) and found that addition of 1–2 equivalents led to the formation of pure greigite nanoparticles between 230 and 280 °C with low SSP concentrations. Average particle size does not vary significantly with increasing concentration, thus providing a convenient route to ca. 40 nm greigite nanoparticles. In situ XAS studies have been carried out and allow a decomposition pathway for [Fe(S2CNiBu2)3] in oleylamine to be established; reduction of Fe(III) to Fe(II) reduction triggers substitution of the secondary amide backbone by oleylamine (RNH2) resulting in the in situ formation of a primary dithiocarbamate derivative [Fe(RNH2)2(S2CNHR)2]. This in turn extrudes RNCS to afford molecular precursors of the observed FeS nanomaterials. The precise role of thiuram disulfide in the decomposition process is unknown, but it likely plays a part in controlling the Fe(III)–Fe(II) equilibrium and may also act as a source of sulfur allowing control over the Fe : S ratio in the mineral products

Simvastatin impairs murine melanoma growth

<p>Abstract</p> <p>Background</p> <p>Statins induces cell cycle arrest, apoptosis, reduction of angiogenic factors, inhibition of the endothelial growth factor, impairing tissue adhesion and attenuation of the resistance mechanisms. The aim of this study was evaluate the anti-tumoral activity of simvastatin in a B16F10 melanoma-mouse model.</p> <p>Methods</p> <p>Melanoma cells were treated with different concentrations of simvastatin and assessed by viability methods. Melanoma cells (5 × 10⁴) were implanted in two month old C57Bl6/J mice. Around 7 days after cells injection, the oral treatments were started with simvastatin (5 mg/kg/day, p.o.). Tumor size, hematological and biochemical analyses were evaluated.</p> <p>Results</p> <p>Simvastatin at a concentration of 0.8 μM, 1.2 μM and 1.6 μM had toxic effect. Concentration of 1.6 μM induced a massive death in the first 24 h of incubation. Simvastatin at 0.8 μM induces early cell cycle arrest in G0/G1, followed by increase of hypodiploidy. Tumor size were evaluated and the difference of treated group and control, after ten days, demonstrates that simvastatin inhibited the tumor expansion in 68%.</p> <p>Conclusion</p> <p>Simvastatin at 1.6 μM, presented cytototoxicity after 72 h of treatment, with an intense death. <it>In vivo</it>, simvastatin being potentially useful as an antiproliferative drug, with an impairment of growth after ten days.</p

Hydrophobicity and Charge Shape Cellular Metabolite Concentrations

What governs the concentrations of metabolites within living cells? Beyond specific metabolic and enzymatic considerations, are there global trends that affect their values? We hypothesize that the physico-chemical properties of metabolites considerably affect their in-vivo concentrations. The recently achieved experimental capability to measure the concentrations of many metabolites simultaneously has made the testing of this hypothesis possible. Here, we analyze such recently available data sets of metabolite concentrations within E. coli, S. cerevisiae, B. subtilis and human. Overall, these data sets encompass more than twenty conditions, each containing dozens (28-108) of simultaneously measured metabolites. We test for correlations with various physico-chemical properties and find that the number of charged atoms, non-polar surface area, lipophilicity and solubility consistently correlate with concentration. In most data sets, a change in one of these properties elicits a ∼100 fold increase in metabolite concentrations. We find that the non-polar surface area and number of charged atoms account for almost half of the variation in concentrations in the most reliable and comprehensive data set. Analyzing specific groups of metabolites, such as amino-acids or phosphorylated nucleotides, reveals even a higher dependence of concentration on hydrophobicity. We suggest that these findings can be explained by evolutionary constraints imposed on metabolite concentrations and discuss possible selective pressures that can account for them. These include the reduction of solute leakage through the lipid membrane, avoidance of deleterious aggregates and reduction of non-specific hydrophobic binding. By highlighting the global constraints imposed on metabolic pathways, future research could shed light onto aspects of biochemical evolution and the chemical constraints that bound metabolic engineering efforts

Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences

During the origin of life, the biological information of nucleic acid polymers must have increased to encode functional molecules (the RNA world). Ribozymes tend to be compositionally unbiased, as is the vast majority of possible sequence space. However, ribonucleotides vary greatly in synthetic yield, reactivity and degradation rate, and their non-enzymatic polymerization results in compositionally biased sequences. While natural selection could lead to complex sequences, molecules with some activity are required to begin this process. Was the emergence of compositionally diverse sequences a matter of chance, or could prebiotically plausible reactions counter chemical biases to increase the probability of finding a ribozyme? Our in silico simulations using a two-letter alphabet show that template-directed ligation and high concatenation rates counter compositional bias and shift the pool toward longer sequences, permitting greater exploration of sequence space and stable folding. We verified experimentally that unbiased DNA sequences are more efficient templates for ligation, thus increasing the compositional diversity of the pool. Our work suggests that prebiotically plausible chemical mechanisms of nucleic acid polymerization and ligation could predispose toward a diverse pool of longer, potentially structured molecules. Such mechanisms could have set the stage for the appearance of functional activity very early in the emergence of life