Session A14: Nonequilibrium Statistical Physics Models of the Origins of Life

Dynamic kinetic stability: Toward the physicalization of biology

Despite the dramatic advances over recent decades in uncovering the physico-chemical basis for life processes, the conceptual gap separating the physical and biological sciences continues to perplex. Life phenomena remain awkwardly incompatible with an accepted physical perspective on material behavior. In this talk I will describe the recent discovery of a previously unrecognized kinetic dimension in chemical space, one offering new insights into the life phenomenon seemingly unavailable through traditional thermodynamic considerations. The kinetic dimension encompasses stable, energy-fueled, non-equilibrium, dynamic chemical systems expressing a distinct stability kind termed dynamic kinetic stability. Recognition of such a stability kind offers physical insights into life’s highly organized non-equilibrium structures and opens up possible strategies for the synthesis of simple proto-life systems. The conceptual gap that has long divided the physical and biological sciences may (hopefully) be beginning to narrow.

 

References

Pascal R & Pross A. Chemistry’s kinetic dimension and the physical basis for life. J Syst Chem 7, 1 (2019).

Pross A & Pascal R. How and why kinetics, thermodynamics, and chemistry induce the logic of biological evolution. Beilstein J. Org. Chem. 13, 665–674 (2017).

    

How informational sequences emerge from random templated ligation

Reduction of the information entropy along with ever-increasing complexity are among the key signatures of life. Understanding the onset of such behavior in the early prebiotic world is essential for solving the problem of the origin of life. In Refs. [1,2] we studied a general problem of heteropolymers capable of template-assisted ligation based on Watson-Crick-like hybridization. The system is driven out of equilibrium by cyclic changes in the environment. We modeled [1] the dynamics of 2-mers, i.e., sequential pairs of specific monomers within the heteropolymer population. While the possible number of them is Z² (where Z is the number of monomer types), we observe that most of the 2-mers eventually get extinct, leaving no more than 2Z survivors. This leads to a dramatic reduction of the information entropy in the sequence space. This natural-selection-like process ultimately results in a limited subset of polymer sequences. Importantly, the set of surviving sequences depends on the initial concentrations of monomers and remains exponentially large (2^L reduced down from Z^L for chains of length L) in each of the realizations. Thus, an inhomogeneity in the initial conditions allows for a massively parallel search of the sequence space for biologically functional polymers, such as ribozymes. The problem has a surprising connection [3] to microbial ecology in which multiple exponentially growing species compete for two types of essential nutrients (e.g., C and N) analogous to Z right and left ends of polymers. Finally, I will describe a recent experimental realization of this system [4] demonstrating the emergence of highly structured sequence motifs, autocatalytic reaction networks, and a dramatic reduction of the information entropy.   

Computer Simulations of Non-Enzymatic Template-Directed RNA Synthesis

The earliest form of RNA replication may have been non-enzymatic, without requiring polymerase ribozymes. Template-directed synthesis of complementary strands forms double strands that are unlikely to separate unless temperature cycling drives melting. If there are multiple copies of identical sequences, re-annealing of existing strands prevents subsequent cycles of copying. However, if there is a diverse mixture of sequences, partially matching sequences can reanneal in configurations that allow continued strand growth. Here we present simulations that incorporate melting, reannealing, primer extension, and ligation. Strand growth occurs over multiple heating/cooling cycles, producing strands over 200 nucleotides in length. However, there is no exact copying of sequences, even if single base additions are fully accurate (no mutational errors). It has been proposed that RNA systems may contain a virtual circular genome consisting of partially overlapping sequences that can be assembled into a circle. We show that this situation is unlikely to arise naturally and cannot maintain itself in the presence of mutational errors or inflow of random oligomers. We show that even a short functional sequence like a tRNA cannot be encoded on a virtual circle because it contains repeated tetramers; hence sequence information on a longer length scale is not maintained. In contrast, we argue that the most likely way for replication to begin in the RNA world involves real circular strands that use the rolling circle mechanism. Multiple copies are produced from a single circle via strand displacement without requiring temperature cycling.   

Towards a Statistical Mechanics of Biochemistry

Life on Earth is unified by its use of a shared set of component chemical compounds and reactions, providing a detailed model for universal biochemistry. This notion of universality is specific to known biochemistry and does not allow quantitative predictions about examples not yet observed. It is also quite different from universality in other fields of research. For example, in statistical physics, universality describes properties or macroscopic features observed across large classes of systems irrespective of the details of any one system. Universality classes are apparent in certain limits where common patterns emerge in the statistics of large numbers of interacting component parts, allowing predictions to be made guiding the search for new examples, as in materials discovery. If biochemistries could be shown to be representative of universality classes in the physical sense, a mechanistic understanding of the identified scaling exponents could have important implications for informing models of new examples of life. Here I introduce a more generalizable concept of biochemical universality, akin to the kind found in physics. Starting from an ensemble of annotated genomic data including 11955 metagenomes, 1282 archaea, 11759 bacteria and 200 eukaryotic taxa, we show universality classes in enzyme functions (Gagler et al., In press 2022), universality in network topology across levels of organization (Kim et al., 2019) and in elemental use and chiral properties of molecules used in biochemical networks (Vergeli et al. In prep, and Kim et al. In prep). These results establish the existence of biochemical universality classes that do not depend strictly on the details of known life's chemistry, with implications for guiding our search for missing biochemical diversity on Earth, or for biochemistries that might deviate from the exact chemical make-up of life-as-we-know-it, such as at the origins of life, in alien environments, or in the design of synthetic life.   

Life originated when physical chemistry ``discovered'' Survival of the Fittest dynamics

What was the origin of life?  Nobody knows.  Some research has sought the answer in the chicken-and-egg question: Which type of molecules came first?  Instead, we believe the answer lies in finding the physico-chemical process(es) that preceded today's Survival of the Fittest (SoF) dynamics.  SoF dynamics is unique.  It is not just positive-feedback autocatalysis.  SoF dynamics entails an autocatalytic coupling of rate processes with population changes.   We have developed a dynamical model that shows that simple random peptide syntheses could have led to peptide chains that elongate, collapse and sometimes fold and catalyze.  These protein processes have the right dynamics as a molecular precursor of Tilman-like ecological Survival of the Fittest.  The model shows how prebiotic catalysts could have become mobile and programmable, generating bio-like diversity of functionalities, taking a step towards living systems.