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Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
1 Correspondence: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: ehudg{at}post.tau.ac.il
ABSTRACT
The molecular basis of the origin of life is one of the most fundamental questions in modern biology. While the "RNA world" hypothesis offers a very sensible model for the evolvement of the current biochemical networks, there is a lack of knowledge about the early steps that led to the formation of the first RNA molecules. This issue is essential as it is practically impossible that complex molecules as functional RNA oligonucleotides had evolved spontaneously. It was recently demonstrated that peptide molecules as simple as dipeptides can self-assemble into well-ordered tubular, fibrilar, and closed-cage structures. Other studies have confirmed the ability of dipeptides to act as catalysts and the capability of other peptides, as short as tripeptides, to serve as a template for nucleotide binding and orientation. Unlike complex RNA molecules, the spontaneous formation of functional short peptides in the primordial earth conditions is very likely. We suggest a novel mechanism for the origin of life that is based on the ability of short peptides to form encapsulated structures, catalyst chemical reaction, and serve as highly ordered template for the assembly of nucleotides. This model may explain the early events that led to the formation of the current biochemical machinery that combines the elaborated and coordinated interaction between nucleic acids and proteins to allow the function of living systems.—Carny, O., Gazit, E. A model for the role of short self-assembled peptides in the very early stages of the origin of life.
Key Words: aromatic interactions • closed-cage nanostructures • molecular recognition • origin of life • peptides • self-association • 
- stacking
THE ENIGMA OF THE ORIGIN OF LIFE on earth 3.7–3.8 billion years ago is one of the major open problems in modern science (1)
. This primordial period bore frequent meteorite hits on the earth surface (2)
. These collisions are assumed to have destroyed all unstable molecules on earth, demolishing origin of life processes (3
, 4)
. The uniformity of the biochemistry and the genetic code in all living organisms clearly implies that all modern organisms that eventually followed these elimination processes descend from a common ancestor (CA). The existence of a unique CA implies there was only a single successful path from which life evolved, thus giving the mechanisms of early chemical evolution a key role. A basic question regarding the development of the CA is how did biological organization evolve from an abiotic supply of small organic molecules?
Two main hypotheses were formulated to explain this problem: the "RNA world" (5)
and the "protein world" (6)
theorems. In consistency with the "protein world" hypothesis, various prebiotic amino acids formation mechanisms were demonstrated under the presumed conditions of primitive earth (7
, 8)
. Alternatively, amino acids could be introduced to the primitive earth by falling meteorites (9)
. Giving the presence of such monomers, it is widely accepted that short peptides could be formed in the primordial soup [e.g., by the salt-induced peptide formation (SIPF) mechanism (10)
] and survive under its harsh conditions. Furthermore, it was argued that peptides could actually self-replicate under these primitive conditions (6)
. However, the great appeal of "RNA world" hypothesis is the chemical functionality of short RNA fragments, on the one hand, together with their superb information storage capacity on the other. Short RNA aptamers can specifically bind various chemical entities (11)
and RNA ribozymes can act as efficient catalysts (12)
. The combination of these qualities can give rise to aptazymes, which can act as sophisticated chemical switches (13)
. These RNA molecules could have served as their own genes, and would have been much simpler to duplicate than proteins. But the "RNA world" theory suffers from an Achilles heel: the instability of the RNA bases in the primordial earth conditions (3)
and the instability of the ribose sugar even under moderate chemical and thermal environments (14)
. Under these limitations, it has been demonstrated that RNA could not sufficiently accumulate to allow RNA-based chemical evolution. To solve this dilemma, it has been suggested there were ancestor polymers to RNA and that these polymers later evolved into RNA (5
, 15)
. This approach is problematic, first because any minute change in the RNA structure would have direct and significant effect on the enzymatic activity of the ribozymes, hence leaving us again with the problem of trying to fill the gap between the pre-RNA world and the existing RNA. Second, since there is no known relic for such a molecule in today’s biological systems, there are no leads as to how such a molecule should be constructed. This represents a major difficulty, considering the vast number of possibilities. In light of these obstacles, the possible roles of peptides as a starting point for the origin of life problem should be examined in a new manner. Origin of life models must form a plausible argument, much as lawyers argue on circumstantial evidence. Plausibility is based on three main considerations: evolutionary continuity, ubiquity of the conditions needed, and robustness of the model without the need of precise environmental parameters (16)
.
We propose a novel mechanism for the origin of life, which satisfy these considerations. Based on recent studies of the self-assembly of very simple peptide motifs and the ability of similar short peptides to bind and recognize with high specificity nucleotides, we suggest a main role for simple peptide self-assembled structures in the stabilization of RNA and in early chemical catalysis. This scenario could later lead to the formation of RNA polymerase as one of the earliest protoenzymes, as has been advocated by others (17
, 18)
. The involvement of short self-assembling peptides in the origin of life has been suggested as potential micelle-forming units (19)
. Here, we extend the hypothesis in light of recent revelations about the abilities of extremely short peptides to either form ordered structures or specifically bind nucleotides, as presented below.
Remarkably short peptides that form amyloid fibrils and other nano-assemblies
Amyloid fibril formation is associated with 
20 major human diseases of unrelated origin. A partial list of amyloid diseases includes Alzheimer’s disease, prion diseases, and type II diabetes (20
, 21)
. These diseases are characterized by the formation of well-organized fibrils in the affected tissues and organs. The formation of the fibrils occurs due to a transition from soluble proteins and polypeptides into an aggregated ß-sheet-rich state. These aggregated structures are not a random cluster of proteins, but extremely well-ordered structures with a typical X-ray fiber diffraction pattern. Despite their formation by a diverse and structurally unrelated group of proteins, all amyloid fibrils share similar biophysical and ultrastructural properties. Moreover, even disease-unrelated proteins can form typical amyloid fibrils with the same molecular properties (22)
. This implies that the amyloid configuration may actually represent an energy-favorable generic state for most proteins (22
, 23)
.
Recent studies identified very short motifs (as short as dipeptide) that are able to self-assemble into amyloid-like fibril structure and/or into nanotubular arrangements (24
25
26
27
28
29
30)
(Fig. 1
). Some of these structures were demonstrated to be hollow and to contain solvents within the core of the assemblies (28
29
30)
. Thus, these structures allow the formation of an isolated aqueous environment that is partially or fully disconnected from the outer space. Moreover, it was demonstrated that similar short peptides could form vesicular closed-cage assemblies that may act as completely isolated environments (28
, 31)
. Some of these self-assembled structures are durable in very harsh environments, including boiling (29)
, high-pressure, and temperature autoclave treatment, and in various organic solvents (unpublished data).
|
The formation of the self-assembled structures by the di- and tripeptides is especially intriguing in the context of the quest for the origin of life. This was the first demonstration that peptides that could undoubtedly spontaneously be formed under primordial condition have all the molecular information to assemble into well-defined encapsulated structures. Several mechanisms of formation could be envisioned. These peptides are clearly short enough to be formed under prebiotic reactions like the SIPF reaction (10)
. As a matter of fact, it was pointed out that the specific sequences of prions, polypeptides that form self-assembled amyloid structures in major maladies such as Creutzfeldt-Jacob disease and bovine spongiform encephalitis, are greatly favored by the SIPF mechanism (32)
. Another possible source for such short di- and tripeptides is outer terrestrial origin. Dipeptides and larger amino acid polymers were found on carbonaceous chondritic meteorites (33
, 34)
. Thus it seems reasonable to assume that such peptides were formed under prebiotic conditions and produced amyloid-related self-assembled structures. Furthermore, a self-replicating and amyloid-forming peptide was recently constructed demonstrating a pathway to the enrichment of such fibrils in the prebiotic world (35)
.
A model for peptide-nucleic acid interactions in the primordial earth
A main question in understanding the origin of life is related to the nature of the first RNA-peptide interactions. This question comes to a plausible solution when considering the characteristics of the previously discussed amyloid and nanotube-forming peptides. It was shown that many amyloid-forming motifs contain aromatic residues, which interact through stacking interactions (25
, 27
, 29
30
31)
. The most notable examples are the formation of nanotubes by the aromatic diphenylalnine peptide (Fig. 1
; refs 29
, 30
) and formation of the aromatic closed-caged vesicles by the diphenylglycine and the Cys-Phe-Phe tripeptide (Fig. 1
; ref 31
). It was assumed that the aromatic stacking interactions may provide energetic contribution as well as order and directionality in the self-assembly of ordered structures (25
, 27
, 29
, 30
, 36)
. This hypothesis was supported by a nonbiased computational work that identified the aromaticity as a clear indicator for the ability of short peptide to form amyloid fibrils (37)
. A recent solid-state NMR study indeed indicated that the molecular organization of the calcitonin amyloid fibrils is consistent with aromatic-stacking interactions (38)
.
These kinds of aromatic stacking interactions are similar to those occurring between nucleic bases and RNA binding proteins (39)
. Thus, short amyloid-forming peptides may also specifically bind nucleotide and nucleic acids. Indeed, it was demonstrated that tripeptides selected from a random peptide library could bind nucleotides with high affinity and specificity (40
, 41)
. A key motif identified by both studies was a combination of a serine or the structurally similar amino acid threonine, together with aromatic amino acids (41)
. Taken together (peptide self-assembly studies and the peptide-nucleotide binding analysis), it is evident that aromatic di- and tripeptides short enough to be formed spontaneously can actually mediate the formation of distinct encapsulated space as well as mediate specific peptide-nucleotide interactions.
As amyloid fibrils are remarkably ordered and repetitive structures with a clear X-ray fiber diffraction, they were considered as 1-dimensional crystals (42)
. This directed crystal growth may give rise to an enantiomeric selectivity in the self-assembly process, a typical characteristic of all biological building blocks. Therefore, these fibrils would exhibit a chiral preference during complexation with other molecules, such as RNA. It was shown that peptides with a very simple secondary structure, including an aromatic cleft, could specifically bind nucleotides (43
, 44)
. Thus, we hypothesize that complexes of RNA, monomers, and polymers with similar peptides organized in an amyloid-related self-assembled conformation could have been formed in a linear fashion preferred directionality and chirality in the primordial soup (Fig. 2
).
|
We suggest that such complexes would have stabilized the RNA under thermal and mechanical pressure, allowing RNA molecules to survive impacts demolishing the origin of life. We also hypothesize that these complexes could have served as template catalysts for the formation of RNA polymers, as it was demonstrated that very short peptides, as short as dipeptides, can catalyze chemical reactions efficiently (45)
. This is a reasonable chemical scenario for the accelerated growth and increased durability of RNA polymers. This mechanism enables the building of supportive chemical evolution between RNA and peptides.
Such an evolutionary process could have given rise to primitive RNA polymerase machinery that functioned as the first enzymes and evolved into the current RNA polymerases, as suggested by Lazcano and his collaborators (17
, 18)
. Support for this hypothesis is found by an examination of contemporary RNA polymerase’s catalytic center, which is responsible for phosphodiester bond formation. This region, highly conserved through evolution, includes the Y/FNADFDGD motif (46)
. This motif contains amino acids that are typical for several amyloidgenic peptides, such as the calcitonin’s amyloidgenic DFNKF motif (25)
and others (27)
. These similarities indicate a possible evolutionary continuity of the primitive self-assembling peptides and current day RNA polymerases.
It was suggested that self-assembled peptide structures could contain small pores (30)
. Such pores might enable small molecules to diffuse into the tube volume but inhibit larger molecule movement. Hence, NTP’s monomers would be able to penetrate the structure whereas RNA oligomers would be blocked inside in a fashion, which recalls Aesop’s fable about "The Swollen Fox." This could give rise to a concentration mechanism of RNA. Thus, NTPs could be formed in the outside media by various prebiotic reactions (5)
and penetrate into the semi-closed structures, which in turn will complex, stabilize, and polymerize these ribonucleotides into oligomers.
The orientation and order of the RNA sequence have been shown to alter the affinities of the stacking interactions (47)
. This characteristic, together with interactions of nearby residues, can give rise to a specific recognition of an RNA sequence with a precise directionality and order, as demonstrated by the ribonucleoprotein domain (RNP). The RNP domain is one of the most common RNA binding domains. It recognizes single-stranded RNA in various structural contexts with a wide range of affinities and specificities (48)
. The binding site of the RNP is an anti-parallel ß-sheet in which the stacking interaction of conserved aromatic residues is crucial for the RNA binding (49)
(Fig. 3
). This structure demonstrates the ability of aromatic residues on a ß-sheet surface to bind RNA in a specific orientation.
|
Model for RNA-peptide mutual chemical evolution
In light of this proposed mechanism, we suggest a new model for early chemical evolution processes. We believe that local accumulations of self-assembling peptide fragments, which formed spontaneously through primordial chemical reactions, produced an "RNA oasis." In this oasis, molecules of RNA could have survived and grow slowly inside a peptide structure functioning as an "RNA factory." In such a system, the instability of the RNA could have been the driving force for its early chemical evolution steps (prereplicating stages). This not only solves the instability problem of the RNA world, but also uses the instability character to explain how the evolutionary process started.
This microenvironment would have given a "Darwinian" advantage to RNA molecules that would catalyst the self-assembled peptides, consequently increasing their fitness, while RNA molecules, which could not be stabilized by the peptide assemblies, would hydrolyze and recover their building blocks back into the "oasis" microenvironment. This is a "step-by-step" process that enables gradual chemical improvements with an evolutionary advantage for every chemical step on the way, as required from any Darwinian development. An RNA molecule that could have catalyzed a peptide bond formation would acquire an advantage over other molecules [e.g., the R180 ribozyme, which catalyzes dipeptide formation (50)
]; thus, a molecule that would have more precise or efficient activity would enrich itself, gradually replacing less fitted molecules, and so forth. Fragments of RNA molecules could form new combinations and arrangements with increased complexity over time. In each generation of fragmentation and repolymerization, enrichment with better stabilized molecules would have occurred. The RNA molecules could have developed a symbiotic community that, by affecting the peptide structures, could have given rise to selectivity in the RNA polymerization process. This could have been an early step in chemical evolution, before the development of self-replicating RNA system (Fig. 4
). Such a self-replicating system could later emerge as an advanced stage in the chemical evolution, after already introducing primitive protein-based enzymes. Thus, this hypothesis also explains the first steps in the development of proteins with enzymatic properties and biological functions.
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CONCLUSIONS
In this paper we presented a novel approach for the problem of the origin of life. This concept deals with the unsolved cardinal issues of the field, such as the "chicken and egg dilemma" regarding the RNA and peptide worlds, RNA instability, the chemical evolution processes before the emergence of replication, and many more. We present a mechanism that holds evolutionary continuity (the development of RNA polymerases), ubiquity, and robustness (depending mostly on the SIPF mechanism and other general prebiotic reactions). Our model predicts the possibility of the existence of stable complexes of RNA and self-assembling peptides. This model and other aspects of this hypothesis are currently being investigated experimentally.
ACKNOWLEDGMENTS
We thank members of the Gazit laboratory for helpful discussion. Support from the Israel Science Foundation (Bikura program) is gratefully acknowledged.
Received for publication October 21, 2004. Accepted for publication February 1, 2005.
REFERENCES
-stacking in the self-assembly of amyloid fibrils. FASEB J. 16,77-83
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