Foldamer hypothesis for the growth and sequence differentiation of prebiotic polymers Elizaveta Gusevaa,b,c, Ronald N. Zuckermannd, and Ken A. Dilla,b,c,1 aLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794; bDepartment of Chemistry, Stony Brook University, Stony Brook, NY 11794; cDepartment of Physics and Astronomy, Stony Brook University, Stony Brook, NY 11794; and dMolecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Contributed by Ken A. Dill, July 10, 2017 (sent for review December 8, 2016; reviewed by Hue Sun Chan and Steve Harvey) It is not known how life originated. It is thought that prebiotic that autocatalytic chain elongation arises from template-assisted processes were able to synthesize short random polymers. How- ligation and random breakage (13). Autocatalytic templating ever, then, how do short-chain molecules spontaneously grow of the self-replication of peptides has also been shown (14, longer? Also, how would random chains grow more informational 15). These are models of the “preinformational” world before and become autocatalytic (i.e., increasing their own concentra- heteropolymers begin to encode biological sequence–structure tions)? We study the folding and binding of random sequences relationships. of hydrophobic (H) and polar (P) monomers in a computational Another class of models describes a “postinformational” het- model. We find that even short hydrophobic polar (HP) chains can eropolymer world, in which there is already some tendency of collapse into relatively compact structures, exposing hydrophobic chains to evolve. In one such model, it is assumed that polymers surfaces. In this way, they act as primitive versions of today’s pro- serve as their own templates because of the ability of certain het- tein catalysts, elongating other such HP polymers as ribosomes eropolymers to concentrate their own precursors (16–19). It sup- would now do. Such foldamer catalysts are shown to form an poses an ability of molecules to recognize “self,” although with- autocatalytic set, through which short chains grow into longer out specifying exactly how. In another such model (20), chains chains that have particular sequences. An attractive feature of undergo sequence-independent template-directed replication. It this model is that it does not overconverge to a single solu- indicates that functional sequences can arise from nonfunctional tion; it gives ensembles that could further evolve under selec- ones through effective exploration of sequence space. These tion. This mechanism describes how specific sequences and con- postinformational models predict that template-directed repli- formations could contribute to the chemistry-to-biology (CTB) cation will enhance sequence diversity (19). These are abstract transition. models of principle that do not specify what particular molecular structures and mechanisms might be autocatalytic. Also, they do origin of life j HP model j biopolymers j autocatalytic sets not address the heteropolymeric or sequence-dependent infor- mational aspects of the chains. mong the most mysterious processes in chemistry is how the There has also been much experimental work leading, for Aspontaneous transition occurred more than 3 billion years example, to the creation of artificial autocatalytic sets in the ago from a soup of prebiotic molecules to living cells. What was laboratory (21–23). Such systems are designed so that pairs of the mechanism of the chemistry-to-biology (CTB) transition? In molecules can catalyze each other (i.e., autocatalysis), leading to this paper, we develop a model to explore how prebiotic polymer- exponential growth of the autocatalytic members. For example, ization processes might have produced long chains of protein- mixtures of RNA fragments are shown to self-assemble sponta- like or nucleic acid-like molecules (1, 2). What polymerization neously into self-replicating ribozymes that can form catalytic processes are autocatalytic? How could they have produced long chains? Also, how might random chain sequences have become informational and self-serving? Our questions here are about Significance physical spontaneous mechanisms, not about specific monomer or polymer chemistries. Today’s lifeforms are based on informational polymers, namely proteins and nucleic acids. It is thought that simple CTB Requires an Autocatalytic Process chemical processes on the early earth could have polymer- Early on, it was recognized that the transition from simple chem- ized monomer units into short random sequences. It is not istry to self-supporting biological behavior requires autocatalysis clear, however, what physical process could have led to the (i.e., some form of positive feedback or bootstrapping, in which next level—to longer chains having particular sequences that the concentrations of some molecules become amplified and self- could increase their own concentrations. We study polymers sustaining relative to other molecules) (3–8). That work has led of hydrophobic and polar monomers, such as today’s proteins. to the idea of an autocatalytic set, a collection of entities in which We find that even some random sequence short chains can any one entity can catalyze another. collapse into compact structures in water, with hydrophobic We first review some of the key results. A class of mod- surfaces that can act as primitive catalysts, and that these els called Graded Autocatalysis Replication Domain (GARD) could elongate other chains. This mechanism explains how (9–11) predicts that artificial autocatalytic chemical kinetic net- random chemical polymerizations could have given rise to works can lead to self-replication, with a corresponding ampli- longer sequence-dependent protein-like catalytic polymers. fication of some chemicals over others. Such systems display some degree of inheritance and adaptability. GARD model Author contributions: R.N.Z. and K.A.D. designed research; E.G. performed research; E.G. is a subset of metabolism first models, which envision that and R.N.Z. analyzed data; and E.G. and K.A.D. wrote the paper. small molecule chemical processes precede information trans- Reviewers: H.S.C., University of Toronto; and S.H., University of Pennsylvania. fer and precede the first biopolymers. Focusing on polymers, The authors declare no conflict of interest. Wu and Higgs (12) developed a model of RNA chain-length Freely available online through the PNAS open access option. autocatalysis. They envision that some of the RNA chains can 1To whom correspondence should be addressed. Email: [email protected]. spontaneously serve as polymerase ribozymes, leading to auto- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. catalytic elongation of other RNAs. A related model asserts 1073/pnas.1620179114/-/DCSupplemental. E7460–E7468 j PNAS j Published online August 22, 2017 www.pnas.org/cgi/doi/10.1073/pnas.1620179114 Downloaded by guest on September 26, 2021 networks that can compete with others (24). One limitation, A PNAS PLUS however, is that these are fragments taken from existing ribozymes, and therefore, they do not explain the origins from more primitive random beginnings. Here, we describe a dynamical mechanism that seeks to bridge from the pre- to postinformational world across the CTB tran- sition. We describe a physical basis for how short chains could have spontaneously led to longer chains, how random chains led to specific sequences, and a structural basis and plausible kinetics for a prebiotic autocatalytic transition. “Flory Length Problem”: Polymerization Processes Produce Mostly Short Chains Prebiotic polymerization experiments rarely produce long chains. It is generally assumed that the prebiotic proteins or nucleic acids that initiated the transition to biology must have been at least 30- to 60-monomers long (25). Both amino acids and nucleotides can polymerize under prebiotic conditions with- B out enzymes, but they produce mostly short chains (26–30). Leman et al. (29) showed that carbonyl sulfide, a simple volcanic gas, brings about the formation of oligopeptides from amino acids under mild conditions in aqueous solution in minutes to hours. However, the products are mainly dimers and trimers. Longer chains can sometimes result through adsorption to clays (31, 32) or minerals (33, 34), from evaporation from tidal pools (35), from concentration in ice through eutectic melts (36), or from freezing (37) or temperature cycling. Even so, the chain- length extensions are modest (38). For example, mixtures of Gly and Gly2 grow to about 6-mers after 14 d (39, 40) on mineral catalysts, such as calcium mont- morillonite, hectorite, silica, or alumina. Or, in the experiments of Kanavarioti et al. (36), polymers of oligouridylates are found up to lengths of 11 bases long, with an average length of 4 after samples of phosphoimidazolide-activated uridine were frozen in the presence of metal ions in dilute solutions. Similar results are found in other polymers: a prebiotically plausible mechanism produces oligomers having a combination of ester and amide Fig. 1. Polymerization processes lead to mostly short chains. (A) Spon- bonds up to length 14 (38). taneous polymerization processes typically lead to a Flory distribution of It is puzzling how prebiotic processes might have overcome chain lengths. Green line gives hli = 6, and blue line corresponds to hli = 2 what we call the Flory Length Problem (i.e., the tendency of any (B) Fitted distributions from experiments