RAF Application. The Origin of Life. E. Bingham 1 L. Hutton-Smith 2 E. Rolls 2. Oxford Summer School in Computational Biology, 2013

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1 The Origin of Life E. Bingham 1 L. Hutton-Smith 2 E. Rolls 2 1 Department of Mathematics University of North Carolina 2 Mathematical Institute University of Oxford Oxford Summer School in Computational Biology, 2013

2 Outline Introduction Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm The Binary Polymer Model The RNA Polymer Model Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys

7 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Beyond science? Maybe not. How did life come to be? 20th century research and the Miller-Urey experiment

8 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Beyond science? Maybe not. How did life come to be? 20th century research and the Miller-Urey experiment

9 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations DNA and proteins Which came first? Chicken and egg problem DNA or proteins? Simultaneous appearance?

12 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations RNA world hypothesis A self supporting/replicating group of molecules Primordial soup However there is criticism

15 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Autocatalytic sets RAF sets could be the answer Autocatalytic set theory plays an important role Informal RAF set definition: A self-sustaining set supported by an abundant food source i.e. every reaction catalysed by at least one molecule in the set And all molecules are generated from a series of reactions leading from the food set

20 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Autocatalytic sets Could they have occurred? Could RAF sets have occurred on the early earth? Abundant creation of the building blocks of life Existence would strengthens prebiotic metabolism theory But did they?

24 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Examples of autocatalytic sets Formose Reactions Polymerisation of cyanide

25 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations Examples of autocatalytic sets Formose Reactions Polymerisation of cyanide

26 Theories for the origin of Life Application of RAF theory to the metabolism first hypothesis RAF application to dynmical simulations RAF application to dynamical simulations Furthering past work Past simulations Binary polymer model Proposed extensions RNA models Realistic reaction networks Dynamics

32 Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm Current dynamical simulations MD and GAUSSIAN Molecular dynamical approach (MD) Newtonian mechanics Electrostatic effects between molecules GAUSSIAN Performs chemistry Calculates electron orbitals

38 Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm Current dynamical simulations Why we didn t want to use these Although accurate Computationally intensive We wish to simulate a large quantity of molecules Unfeasible

42 Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm What sort of simulation is feasible? i.e. will finish before the expansion of the sun Toy chemistries WillieWorld Does not implement quantum mechanics Performs chemistry through a set of rules Mixing a molecular construction kit Free radicals

48 Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm WillieWorld

49 Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm Why not use Willie World? Far from chemical realism Creation of unrealistic molecules Arguably a step in the right direction However developing the model to include more realism in the time was unrealistic Random motion With no other dynamical effects the system was redundant compared to purely stochastic processes Computationally more reasonable Gillespie algorithm

57 Molecular Dynamical and Quantum simulations Toy chemistries and Willie World The Gillespie Algorithm The Gillespie Algorithm Stochastic dynamical method Calculates the probability of a reaction based on parameters Concentrations of the reactants Rate of the reaction From the weighted probabilities of the different reactions one is chosen to occur The system then moves forward in time This process is repeated until the system reached the prescribed end time

63 The Binary Polymer Model The RNA Polymer Model Preliminary work on the Binary Polymer model The previously mentioned Binary polymer model used in past research Litigation and cleavage reactions Precursor to the RNA Polymer Model

66 The Binary Polymer Model The RNA Polymer Model The Binary Polymer Model Assigning catalysis Random Template based catalysis Similar work by Filisetti et al. 2011

69 The Binary Polymer Model The RNA Polymer Model What the model is Effectively the quarternary polymer model, with base elements A, C, G, U Use RNAfold to generate secondary structure Define catalysis

72 The Binary Polymer Model The RNA Polymer Model Catalysis explanation

73 The Binary Polymer Model The RNA Polymer Model Doing a combinatorial expansion of a subset of the possible reaction system Start with a small initial starting set Combinatorially expand

74 The Binary Polymer Model The RNA Polymer Model Doing a combinatorial expansion of a subset of the possible reaction system Start with a small initial starting set Combinatorially expand

75 The Binary Polymer Model The RNA Polymer Model RNA Polymer Preliminary Results RAF sets sought on reaction system with 25,000 molecules and 50,000 reactions 72 systems generated Found phase shifts Mid-point of phase shift at around 8.5 catalysations per molecule

79 The Binary Polymer Model The RNA Polymer Model Example of a system s results

80 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Motivation Previous models, especially the Binary polymer model, lack chemical realism We will discuss the possibilities to add chemical properties In order to investigate the existence of RAF sets and the impact of more realistic network topology

83 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Simple rule based simulation Our first idea was essentially an expansion of the concept of Willie world Implementing the Gillespie algorithm Over tracking individual random motion of particles We would use toy atoms and valance based properties Covalent and ionic bonding The system would populate a possible reactions based on comparing free radicals on molecules

89 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Issues with this approach As good, if not better, than Willie World Open to the addition of complexity Including enough rules to make accurate would be an increasingly inefficient task

92 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys The Graph Grammar Library GGL A generic framework for rewriting networks of graphs based on specified rules on transformations between subgraphs A chemical reaction can be viewed as graph transformation from the set of reactant graphs set of product graphs Iterative expansion the topology of chemical reaction network from: A set of chemical reactions (graph rewrite rules) Set of molecules (vertex and edge labeled graphs) We could then using the GGL to generate a full reaction network based on initial system conditions and the rules With this we could simulate chemical reactions with the Gillespie algorithm

99 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Rule encoding with GGL The rules within GGL can be extremely general As the GGL examines subgraphs within graphs It can be instructed to look for a particular feature of a molecule and transform it For example, open chain molecules to cyclic molecules, polymerizations These types of transformations were not possible in Willie World Eases the creation of a large reaction network

105 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Constructing RNA A molecular biologists dream The outlines for proposed reactions leading to the construction of RNA through various chemical reactions are laid out in a paper by Leslie E. Orgel We aimed to analyse these chemical reaction to add rules to the GGL engine We soon discovered that within the time available it would be impossible to make these rules general enough Without which any simulation of a primordial soup would seriously lack realism The simulation would simply perform the proposed rules for the creation of RNA, no matter how unlikely this would be in practice We clearly needed a more encompassing method of performing chemistry

110 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Creating a realistic reaction network A different approach The problem we had been encountering was essentially, how do to create a reaction system with was close to reality We chose to not decide what can react with what within our system, but to consult chemical databases. This would bring a level of chemical realism far greater than any of the previously described models Also this would give a much wider scope of possible paths within the system

114 Simple valency model GGL and prebiotic metabolism networks Reaction networks using Reaxys Reaxys A chemical database By outputting reaction data from the chemical database Reaxys we intended to create a reaction network We wanted this to be close to an early Earth environment Previous work on this had yielded a list of small molecules thought to be fundamental to the OOL We used these as our food set We performed iterations with these molecules with Reaxys From this we managed to obtain a reaction network derived from our food set to apply the Gillespie algorithm

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