Balázs Könnyű

The dynamics of the RNA world: insights and challenges

The RNA world hypothesis of the origin of life, in which RNA emerged as both enzyme and information carrier, is receiving solid experimental support. The prebiotic synthesis of biomolecules, the catalytic aid offered by mineral surfaces, and the vast enzymatic repertoire of ribozymes are only pieces of the origin of life puzzle; the full picture can only emerge if the pieces fit together by either following from one another or coexisting with each other. Here, we review the theory of the origin, maintenance, and enhancement of the RNA world as an evolving population of dynamical systems. The dynamical view of the origin of life allows us to pinpoint the missing and the not fitting pieces: (1) How can the first self‐replicating ribozyme emerge in the absence of template‐directed information replication? (2) How can nucleotide replicators avoid competitive exclusion despite utilizing the very same resources (nucleobases)? (3) How can the information catastrophe be avoided? (4) How can enough genes integrate into a cohesive system in order to transition to a cellular stage? (5) How can the way information is stored and metabolic complexity coevolve to pave to road leading out of the RNA world to the present protein–DNA world?

Gag-Pol Processing during HIV-1 Virion Maturation: A Systems Biology Approach

Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates; multiple enzyme forms; PR auto-processing), which calls for a systems level approach to identify key vulnerabilities and optimal treatment strategies. Here we present the first full reaction kinetics model of proteolytic processing by HIV-1 PR, taking into account all canonical cleavage sites within Gag and Gag-Pol, intermediate products and enzyme forms, enzyme dimerization, the initial auto-cleavage of full-length Gag-Pol as well as self-cleavage of PR. The model allows us to identify the rate limiting step of virion maturation and the parameters with the strongest effect on maturation kinetics. Using the modelling framework, we predict interactions and compensatory potential between individual cleavage rates and drugs, characterize the time course of the process, explain the steep dose response curves associated with PR inhibitors and gain new insights into drug action. While the results of the model are subject to limitations arising from the simplifying assumptions used and from the uncertainties in the parameter estimates, the developed framework provides an extendable open-access platform to incorporate new data and hypotheses in the future.

The Evolution of Enzyme Specificity in the Metabolic Replicator Model of Prebiotic Evolution

The chemical machinery of life must have been catalytic from the outset. Models of the chemical origins have attempted to explain the ecological mechanisms maintaining a minimum necessary diversity of prebiotic replicator enzymes, but little attention has been paid so far to the evolutionary initiation of that diversity. We propose a possible first step in this direction: based on our previous model of a surface-bound metabolic replicator system we try to explain how the adaptive specialization of enzymatic replicator populations might have led to more diverse and more efficient communities of cooperating replicators with two different enzyme activities. The key assumptions of the model are that mutations in the replicator population can lead towards a) both of the two different enzyme specificities in separate replicators: efficient “specialists” or b) a “generalist” replicator type with both enzyme specificities working at less efficiency, or c) a fast-replicating, non-enzymatic “parasite”. We show that under realistic trade-off constraints on the phenotypic effects of these mutations the evolved replicator community will be usually composed of both types of specialists and of a limited abundance of parasites, provided that the replicators can slowly migrate on the mineral surface. It is only at very weak trade-offs that generalists take over in a phase-transition-like manner. The parasites do not seriously harm the system but can freely mutate, therefore they can be considered as pre-adaptations to later, useful functions that the metabolic system can adopt to increase its own fitness.

Spatial aspects of prebiotic replicator coexistence and community stability in a surface-bound RNA world model

BackgroundThe coexistence of macromolecular replicators and thus the stability of presumed prebiotic replicator communities have been shown to critically depend on spatially constrained catalytic cooperation among RNA-like modular replicators. The necessary spatial constraints might have been supplied by mineral surfaces initially, preceding the more effective compartmentalization in membrane vesicles which must have been a later development of chemical evolution.ResultsUsing our surface-bound RNA world model – the Metabolic Replicator Model (MRM) platform – we show that the mobilities on the mineral substrate surface of both the macromolecular replicators and the small molecules of metabolites they produce catalytically are the key factors determining the stable persistence of an evolvable metabolic replicator community.ConclusionThe effects of replicator mobility and metabolite diffusion on different aspects of replicator coexistence in MRM are determined, including the maximum attainable size of the metabolic replicator system and its resistance to the invasion of parasitic replicators. We suggest a chemically plausible hypothetical scenario for the evolution of the first protocell starting from the surface-bound MRM system.

Ecology and Evolution in the RNA World Dynamics and Stability of Prebiotic Replicator Systems

As of today, the most credible scientific paradigm pertaining to the origin of life on Earth is undoubtedly the RNA World scenario. It is built on the assumption that catalytically active replicators (most probably RNA-like macromolecules) may have been responsible for booting up life almost four billion years ago. The many different incarnations of nucleotide sequence (string) replicator models proposed recently are all attempts to explain on this basis how the genetic information transfer and the functional diversity of prebiotic replicator systems may have emerged, persisted and evolved into the first living cell. We have postulated three necessary conditions for an RNA World model system to be a dynamically feasible representation of prebiotic chemical evolution: (1) it must maintain and transfer a sufficient diversity of information reliably and indefinitely, (2) it must be ecologically stable and (3) it must be evolutionarily stable. In this review, we discuss the best-known prebiotic scenarios and the corresponding models of string-replicator dynamics and assess them against these criteria. We suggest that the most popular of prebiotic replicator systems, the hypercycle, is probably the worst performer in almost all of these respects, whereas a few other model concepts (parabolic replicator, open chaotic flows, stochastic corrector, metabolically coupled replicator system) are promising candidates for development into coherent models that may become experimentally accessible in the future.

Phenotype/genotype sequence complementarity and prebiotic replicator coexistence in the metabolically coupled replicator system

BackgroundRNA or RNA-like polymers are the most likely candidates for having played the lead roles on the stage of the origin of life. RNA is known to feature two of the three essential functions of living entities (metabolism, heredity and membrane): it is capable of unlimited heredity and it has a proven capacity for catalysing very different chemical reactions which may form simple metabolic networks. The Metabolically Coupled Replicator System is a class of simulation models built on these two functions to show that an RNA World scenario for the origin of life is ecologically feasible, provided that it is played on mineral surfaces. The fact that RNA templates and their copies are of complementary base sequences has an obvious dynamical relevance: complementary strains may have very different structures and, consequently, functions – one may specialize for increasing enzymatic activity while the other takes the role of the gene of the enzyme.ResultsIncorporating the functional divergence of template and copy into the Metabolically Coupled Replicator System model framework we show that sequence complementarity 1) does not ruin the coexistence of a set of metabolically cooperating replicators; 2) the replicator system remains resistant to, but also tolerant with its parasites; 3) opens the way to the evolutionary differentiation of phenotype and genotype through a primitive version of phenotype amplification.ConclusionsThe functional asymmetry of complementary RNA strains results in a shift of phenotype/genotype (enzyme/gene) proportions in MCRS, favouring a slight genotype dominance. This asymmetry is expected to reverse due to the evolved trade-off of high “gene” replicability and high catalytic activity of the corresponding “enzyme” in expense of its replicability. This trade-off is the first evolutionary step towards the “division of labour” among enzymes and genes, which has concluded in the extreme form of phenotype amplification characteristic of our recent DNA-RNA-protein World.

In silico ribozyme evolution in a metabolically coupled RNA population

BackgroundThe RNA World hypothesis offers a plausible bridge from no-life to life on prebiotic Earth, by assuming that RNA, the only known molecule type capable of playing genetic and catalytic roles at the same time, could have been the first evolvable entity on the evolutionary path to the first living cell. We have developed the Metabolically Coupled Replicator System (MCRS), a spatially explicit simulation modelling approach to prebiotic RNA-World evolution on mineral surfaces, in which we incorporate the most important experimental facts and theoretical considerations to comply with recent knowledge on RNA and prebiotic evolution. In this paper the MCRS model framework has been extended in order to investigate the dynamical and evolutionary consequences of adding an important physico-chemical detail, namely explicit replicator structure – nucleotide sequence and 2D folding calculated from thermodynamical criteria – and their possible mutational changes, to the assumptions of a previously less detailed toy model.ResultsFor each mutable nucleotide sequence the corresponding 2D folded structure with minimum free energy is calculated, which in turn is used to determine the fitness components (degradation rate, replicability and metabolic enzyme activity) of the replicator. We show that the community of such replicators providing the monomer supply for their own replication by evolving metabolic enzyme activities features an improved propensity for stable coexistence and structural adaptation. These evolutionary advantages are due to the emergent uniformity of metabolic replicator fitnesses imposed on the community by local group selection and attained through replicator trait convergence, i.e., the tendency of replicator lengths, ribozyme activities and population sizes to become similar between the coevolving replicator species that are otherwise both structurally and functionally different.ConclusionsIn the most general terms it is the surprisingly high extra viability of the metabolic replicator system that the present model adds to the MCRS concept of the origin of life. Surface-bound, metabolically coupled RNA replicators tend to evolve different, enzymatically active sites within thermodynamically stable secondary structures, and the system as a whole evolves towards the robust coexistence of a complete set of such ribozymes driving the metabolism producing monomers for their own replication.ReviewersThis article was reviewed by Gáspár Jékely, Anthony Poole and Armen Mulkidjanian

Template Directed Replication Supports the Maintenance of the Metabolically Coupled Replicator System

The RNA World scenario of prebiotic chemical evolution is among the most plausible conceptual framework available today for modelling the origin of life. RNA offers genetic and catalytic (metabolic) functionality embodied in a single chemical entity, and a metabolically cooperating community of RNA molecules would constitute a viable infrabiological subsystem with a potential to evolve into proto-cellular life. Our Metabolically Coupled Replicator System (MCRS) model is a spatially explicit computer simulation implementation of the RNA-World scenario, in which replicable ribozymes cooperate in supplying each other with monomers for their own replication. MCRS has been repeatedly demonstrated to be viable and evolvable, with different versions of the model improved in depth (chemical detail of metabolism) or in extension (additional functions of RNA molecules). One of the dynamically relevant extensions of the MCRS approach to prebiotic RNA evolution is the explicit inclusion of template replication into its assumptions, which we have studied in the present version. We found that this modification has not changed the behaviour of the system in the qualitative sense, just the range of the parameter space which is optimal for the coexistence of metabolically cooperating replicators has shifted in terms of metabolite mobility. The system also remains resistant and tolerant to parasitic replicators.