Research on the origin of life is highly heterogeneous. After a peculiar historical development, it still includes strongly opposed views which potentially hinder progress. In the 1st Interdisciplinary Origin of Life Meeting, early-career researchers gathered to explore the commonalities between theories and approaches, critical divergence points, and expectations for the future. We find that even though classical approaches and theories—e.g., bottom-up and top-down, RNA world vs. metabolism-first—have been prevalent in origin of life research, they are ceasing to be mutually exclusive and they can and should feed integrating approaches. Here we focus on pressing questions and recent developments that bridge the classical disciplines and approaches, and highlight expectations for future endeavours in origin of life research.

Iron‐sulfur clusters are thought to be ancient cofactors that could have played a role in early protometabolic systems. Thus far, redox active, prebiotically plausible iron‐sulfur clusters have always contained cysteine ligands to the cluster. However, extant iron‐sulfur proteins can be found to exploit other modes of binding, including ligation by histidine residues, as seen with [2Fe‐2S] Rieske and MitoNEET proteins. Here, we investigated the ability of cysteine‐ and histidine‐containing peptides to coordinate a mononuclear Fe²⁺ center and a [2Fe‐2S] cluster and compare their properties with purified iron‐sulfur proteins. The iron‐sulfur peptides were characterized by UV‐vis, circular dichroism, and paramagnetic NMR spectroscopies and cyclic voltammetry. Small (≤6 amino acids) peptides can coordinate [2Fe‐2S] clusters through a combination of cysteine and histidine residues with similar reduction potentials as their corresponding proteins. Such complexes may have been important for early cell‐like systems.

HapX and SreA are transcription factors that regulate the response of the fungus Aspergillus fumigatus to the availability of iron. During iron starvation, HapX represses genes involved in iron consuming pathways and upon a shift to iron excess, HapX activates these same genes. SreA blocks the expression of genes needed for iron uptake during periods of iron availability. Both proteins possess cysteine‐rich regions (CRR) that are hypothesized to be necessary for the sensing of iron levels. However, the contribution of each of these domains to the function of the protein has remained unclear. Here, the ability of peptide analogs of each CRR is determined to bind an iron‐sulfur cluster in vitro. UV–vis and resonance Raman (RR) spectroscopies reveal that each CRR is capable of coordinating a [2Fe‐2S] cluster with comparable affinities. The iron–sulfur cluster coordinated to the CRR‐B domain of HapX displays particularly high stability. The data are consistent with HapX and SreA mediating responses to cellular iron levels through the direct coordination of [2Fe‐2S] clusters. The high stability of the CRR‐B peptide may also find use as a starting point for the development of new green catalysts.

Greater concentrations of hydrosulfide lead to the prebiotic formation of higher nuclearity Fe–S peptides, culminating in a putative nitrogenase-like [6Fe–9S] cluster. Higher nuclearity clusters are more stable with lower reduction potential.

The transition from unregulated, prebiotic chemistry to metabolic-like systems capable of supporting an evolving protocell has remained difficult to explain. One hypothesis is that early catalysts began to prune the chemical landscape in a manner that facilitated the emergence of modern-day enzymes. As enzymes frequently rely on the intrinsic reactivity of metal ions, it follows that these early catalysts may have been metal ions coordinated to prebiotic peptides that have remained as core structures within extant proteins. Here, we demonstrate that UV light directly selects for the types of metal-binding peptide motifs found in biology. This is because bare cysteine is much more susceptible to photolysis than cysteine bound by a metal ion. Therefore, peptides with greater affinity for environmentally available metal ions, such as Fe²⁺ or Zn²⁺, are more stable. Our results are supported by mass spectrometry, calorimetry, X-ray absorption, NMR spectroscopy, transient absorption pump probe spectroscopy, and excited-state quantum-chemical calculations. Photostability arises from the ability of the metal ion to engage transiently generated reactive radical centers in a manner that prevents subsequent degradative processes. The data are consistent with the enrichment of a restricted set of high affinity, extant-like metallopeptides in surficial environments on the early Earth.