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Numerous long-standing questions in origins-of-life research center on the history of biopolymers. For example, how and why did nature select the polypeptide backbone and proteinaceous side chains? Depsipeptides, containing both ester and amide linkages, have been proposed as ancestors of polypeptides. In this paper, we investigate cationic depsipeptides that form under mild dry-down reactions. We compare the oligomerization of various cationic amino acids, including the cationic proteinaceous amino acids (lysine, Lys; arginine, Arg; and histidine, His), along with nonproteinaceous analogs of Lys harboring fewer methylene groups in their side chains. These analogs, which have been discussed as potential prebiotic alternatives to Lys, are ornithine, 2,4-diaminobutyric acid, and 2,3-diaminopropionic acid (Orn, Dab, and Dpr). We observe that the proteinaceous amino acids condense more extensively than these nonproteinaceous amino acids. Orn and Dab readily cyclize into lactams, while Dab and Dpr condense less efficiently. Furthermore, the proteinaceous amino acids exhibit more selective oligomerization through their α-amines relative to their side-chain groups. This selectivity results in predominantly linear depsipeptides in which the amino acids are α-amine-linked, analogous to today's proteins. These results suggest a chemical basis for the selection of Lys, Arg, and His over other cationic amino acids for incorporation into proto-proteins on the early Earth. Given that electrostatics are key elements of protein-RNA and protein-DNA interactions in extant life, we hypothesize that cationic side chains incorporated into proto-peptides, as reported in this study, served in a variety of functions with ancestral nucleic acid polymers in the early stages of life.

Appropriate positioning and the judicious choice of nearby amino acid residues are demonstrated to lead to >900-fold differences in reactivity of otherwise identical functional groups in short peptides. The described ribosomes and nonribosomal peptide synthetases active site models do not approach the efficiencies of natural enzymes.

A study was conducted in which internal cavities of different sizes and polarities were characterized in a series of parallel and antiparallel coiled-coil tetramers. These three-dimensional structures illustrate some of the varied surfaces that can be constructed in closely related peptides with very similar overall folds and may provide a basis for the future design of de novo helical proteins.

The design and functional characterizations of short alpha-helical peptides that mimic the aminoacyl loading and intermodular aminoacyl transfer steps of nonribosomal peptide synthetases (NRPS) with aminolysis rate enhancements in neutral aqueous solutions up to 5400-fold are discussed. The analysis reveals that the helix subunit exchange rates are faster than the rate of intermodular aminoacyl transfer.

The reactions of carbonyl sulfide (COS) are investigated in the context of phosphate activation in neutral aqueous solutions. The results have shown that COS, a simple volcanic gas, can mediate both phosphoryl transfer and peptide synthesis reaction via a single intermediate, aminoacyl N-carboxy-anhydride, under mild aqueous conditions on the prebiotic Earth.

Although thioacids have been proposed as acylating agents and energy carriers in the context of prebiotic chemical evolution, there has been little exploration of their synthesis in an aqueous, abiotic setting. Here we report that α-amino thioacids are generated from α-amino acids in water in the presence of carbonyl sulfide (COS), a component of volcanic and deep sea vent emissions. Traces of thioacid are formed when amino acids react with COS alone in water, with the required sulfide presumably originating from COS decomposition. Higher yields of thioacid are observed when sulfide ions are added exogenously to the reactions. The proposed mechanism involves activation of the amino acid to an N-carboxyanhydride (NCA) mediated by COS. Our data shows that COS also catalyzes the hydrolysis of α-amino thioacids, so the observed yields are a net of thioacid synthesis and breakdown. Although the NCA has been a topic of research for decades, this is the first report to our knowledge of NCA-mediated thioacid formation in water. These findings broaden the scope of reactions mediated by COS, suggesting a mechanism by which peptide formation, phosphate activation and phosphorylation, and the syntheses of aminoacyl thioacids, could have shared a common pathway on the prebiotic Earth. [ABSTRACT FROM AUTHOR]

Certain amphipathic α-helicalpeptides can functionally mimicmany of the properties of full-length apolipoproteins, thereby offeringan approach to modulate high-density lipoprotein (HDL) for combatingatherosclerosis. In this Perspective, we summarize the key findingsand advances over the past 25 years in the development of peptidesthat mimic apolipoproteins, especially apolipoprotein A-I (apoA-I).This assemblage of information provides a reasonably clear pictureof the state of the art in the apolipoprotein mimetic field, an appreciationof the potential for such agents in pharmacotherapy, and a sense ofthe opportunities for optimizing the functional properties of HDL. [ABSTRACT FROM AUTHOR]

Catalytic RNAs (ribozymes) were central to early stages of life on earth. The first ribozymes probably emerged in the presence of prebiotically generated peptides because amino acids can be generated under abiotic conditions, and amino acids can oligomerize into peptides under prebiotically plausible conditions. Here we tested whether the presence of prebiotically plausible peptides could have aided the emergence of ribozymes, by an in vitro selection of self-triphosphorylation ribozymes from random sequence in the presence of ten different octapeptides. These peptides were composed of ten different, prebiotically plausible amino acids, each as mixture of d- and l-stereoisomers. After five rounds of selection and high throughput sequencing analysis, ten ribozymes that appeared most promising for peptide benefits were tested biochemically for possible benefits from each of the ten peptides. The strongest peptide benefit enhanced ribozyme activity by 2.6-fold, similar to the effect from an increase in the pH by one-half unit. Four arbitrarily chosen ribozymes from a previous selection without peptides showed no significant change in their activity in the presence of the ten peptides. Therefore, the used prebiotically plausible peptides - peptides without evolutionarily optimized sequence, without cationic or aromatic side chains - did not provide a strong benefit for the emergence of ribozyme activity. This finding stands in contrast to previously identified polycationic peptides, conjugates between peptides and polyaromatic hydrocarbons, and modern mRNA encoded proteins, all of which can strongly increase ribozyme function. The results are discussed in the context of origins of life., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)