chemart / rna-folding-ac

hub:
  repo_type: generator
  builtin: rna-folding-ac
  tags:
  - banzhaf-yamamoto
chemistries:
- id: rna-folding-ac
  name: RNA-folding ribozyme artificial chemistry
  intuition: 'The most physically real chemistry in the catalog. Molecules are RNA sequences, and each
    one is folded by actual free-energy minimisation into a secondary structure; the structure''s largest
    loop is then read as the reaction that molecule catalyses. So genotype determines phenotype determines
    function, with the middle step done by thermodynamics rather than by a lookup table. It also exhibits
    the property that makes RNA landscapes special: vast neutral networks, where many mutations leave
    the fold and hence the function unchanged.

    '
  aliases:
  - Ullrich-Flamm ribozyme metabolism
  - sequence-to-function map for ribozyme-catalyzed metabolisms
  origin: Ullrich & Flamm, 2008
  book: 18.1.1
  refs:
  - '[873]'
  - '[874]'
  - '[875]'
  - '[876]'
  - '[280]'
  - '[349]'
  - '[389]'
  - '[390]'
  - '[300]'
  - '[103]'
  family: systems-biology
  kind: generator
  constructive: true
  S:
    repr: RNA sequences over AUGC, each folded by free-energy minimisation (Vienna RNA) into a secondary
      structure in dot-bracket notation; Species.structure holds 'sequence dot-bracket'
    definition: implicit
  R:
    definition: implicit
    arity:
    - 2
    - 3
    scheme: 'Two-step genotype->phenotype->function map: sequence -> MFE structure -> catalytic function
      read off the longest loop, interpreted as the imaginary transition structure (ITS) of the catalysed
      reaction. A mono-cyclic ITS of size 2n alternates n broken and n formed bonds, so only even loop
      cycles are catalytic; one stem (hairpin) gives cleavage E + X -> E + Y + Z, two stems (interior/bulge)
      give ligation E + Y + Z -> E + X. The ribozyme binds the Watson-Crick reverse complement of its
      loop sequence.

      '
  A:
    reactor:
    - well-stirred-multiset
    - graph-rewrite
    dilution: closure mode is cut off by max_species; the well-stirred run optionally dilutes back to
      the initial population size
  params:
  - name: seq_length
    type: int
    default: 30
    min: 8
    max: 120
    role: structural
    meaning: length of each RNA sequence in the initial pool
    range: Flamm et al. (2010) use tRNA-size genes of 100 nt carried on a 5000 nt genome
  - name: pool
    type: int
    default: 8
    min: 1
    max: 200
    role: population
    meaning: number of random RNA sequences the run starts from
    range: well-stirred mode needs at least 3; paper-scale runs hold tens of ribozymes per cell
  - name: mode
    type: enum
    default: closure
    choices:
    - closure
    - well-stirred
    role: structural
    meaning: 'closure: every reaction reachable from the pool; well-stirred: the reactions that fired
      in a multiset run, with counts'
  - name: max_species
    type: int
    default: 60
    min: 2
    max: 5000
    role: structural
    meaning: species budget for the closure; the network is reported as truncated when it is reached
  - name: steps
    type: int
    default: 500
    min: 1
    max: 200000
    role: population
    meaning: number of collisions in the well-stirred run
  - name: dilution
    type: enum
    default: none
    choices:
    - none
    - constant
    role: population
    meaning: whether the well-stirred population is diluted back to its initial size after every reaction
  - name: its_min
    type: int
    default: 4
    min: 2
    max: 200
    role: structural
    meaning: smallest ITS size (longest-loop cycle length) that is catalytic
  - name: its_max
    type: int
    default: 12
    min: 2
    max: 200
    role: structural
    meaning: largest ITS size that is catalytic; larger loops are treated as composite transition structures
  - name: min_recognition
    type: int
    default: 3
    min: 1
    max: 50
    role: structural
    meaning: length of the recognition word read off the loop sequence (level 4 of the ITS hierarchy,
      the atom types)
  - name: min_fragment
    type: int
    default: 2
    min: 1
    max: 50
    role: structural
    meaning: shortest fragment a cleavage may produce
  provides:
  - topology
  - stoichiometry
  - catalysts
  - energies
  - mass-conservation
  - initial-state
  - sequence-structure-function
  fidelity: reconstructed
  sources:
  - 'Flamm, C., Ullrich, A., Ekker, H., Mann, M., Hogerl, D., Rohrschneider, M., Sauer, S., Scheuermann,
    G., Klemm, K., Hofacker, I.L. & Stadler, P.F. (2010). Evolution of metabolic networks: a computational
    frame-work. Journal of Systems Chemistry 1:4. Open access, https://doi.org/10.1186/1759-2208-1-4 -
    sections ''Ribozyme Catalysis'' and ''Artificial Molecular Biology'' are the specification used here.'
  - Banzhaf, W. & Yamamoto, L. (2015). Artificial Chemistries, section 18.1.1 and table 18.1 (MIT Press).
  - Ullrich, A. & Flamm, C. (2008). Functional evolution of ribozyme-catalyzed metabolisms in a graph-based
    toy-universe. CMSB, LNCS 5307:28-43. https://doi.org/10.1007/978-3-540-88562-7_7 (abstract and introduction
    only; the full chapter is paywalled).
  - Ullrich, A. & Flamm, C. (2009). A sequence-to-function map for ribozyme-catalyzed metabolisms. ECAL,
    LNCS 5778:19-26. https://doi.org/10.1007/978-3-642-21314-4_3 (abstract and introduction only; the
    full chapter is paywalled).
  - Fujita, S. (1986). Description of organic reactions based on imaginary transition structures. J. Chem.
    Inf. Comput. Sci. 26(4):205-230 - the ITS cycle alternates broken and formed bonds, hence the even-size
    criterion.
  - Hofacker, I.L., Fontana, W., Stadler, P.F., Bonhoeffer, S., Tacker, M. & Schuster, P. (1994). Fast
    folding and comparison of RNA secondary structures. Monatshefte fur Chemie 125:167-188 - the folding
    routines (ViennaRNA 2.7.2 is used here).
  decisions:
  - 'The book describes this AC in prose only. The model is reconstructed from Flamm et al. (2010), which
    states the map verbatim: sequence -> MFE structure (Vienna RNA) -> the longest loop read as the ITS,
    with the ITS size given by the loop length, the stems fixing the arrangement of the electron re-ordering,
    and the sequence inside the loop fixing the atom types.'
  - 'Loop length is implemented as the length of the loop cycle in the structure graph: unpaired bases
    plus the two bases of every delimiting pair. This is the cycle whose size Fujita counts as the number
    of atoms in the electron re-ordering; the exterior loop is not a cycle and is excluded.'
  - 'Catalytic criterion: a mono-cyclic ITS of size 2n breaks n and forms n bonds alternately (Fujita
    1986), so only even cycle sizes are catalytic, within [its_min, its_max]. Multiloops (three or more
    stems) are composite transition structures and are inert here.'
  - 'Which concrete reaction each ITS class denotes is specified in Ullrich''s Leipzig PhD thesis and
    in the paywalled CMSB/ECAL chapters, none of which could be obtained. Chemart therefore fixes the
    two canonical ribozyme reactions by stem count: hairpin loops (one stem) cleave, interior and bulge
    loops (two stems) ligate. This is Chemart''s choice, not a published rule.'
  - 'The original model rewrites ToyChem metabolite graphs and derives rate constants from activation
    energies (QSPR). ToyChem''s extended-Huckel chemistry is out of scope here, so the ribozymes act on
    RNA sequences themselves: the recognition site is the Watson-Crick reverse complement of the first
    min_recognition bases of the loop sequence, cleavage cuts immediately 3'' of that site, and ligation
    joins two molecules whose junction spells it. No rate constants are published that this implementation
    could reproduce, so every reaction carries rate None.'
  - Defaults are small (30 nt, 4 seed sequences, 60 species) so that the closure folds in well under a
    second; the paper's scale (100 nt genes, 5000 nt genomes, 100-1000 generations) is recorded in the
    params' range fields.
  - Book table 18.1 gives two 60 nt sequences with their RNAfold structures. ViennaRNA 2.7.2 reproduces
    the second exactly (-7.10 kcal/mol); for the first it returns a different structure at -10.90 kcal/mol,
    while the book's structure evaluates to -9.80 and appears in the 1.5 kcal/mol suboptimal ensemble.
    The book's first structure is therefore suboptimal under current Turner parameters (identical under
    Turner 1999 and 2004); the tests record both facts.
  reference_impl: Graph Grammar Library (GGL), http://www.tbi.univie.ac.at/software.html - the original
    toolchain (ToyChem + GGL), not ported here
  phenomena:
  - 'large neutral networks in genotype space: a large fraction of point mutants fold to the same structure,
    so the map is simultaneously robust and evolvable'
  - a variety of alternative functions is reachable within a short distance in sequence space
  - small-world connectivity with highly connected hub metabolites in large evolved networks
  - 'phased evolution: forward extension of pathways that break food molecules down first, enzyme recruitment
    and specialisation later'
  notes: 'The most ''realistic'' generator in the book: real thermodynamic folding driving the genotype-phenotype
    map. Chemart implements the folding and the sequence-to-function map faithfully and substitutes RNA
    cleavage/ligation for the ToyChem graph rewriting, so the network is a ribozyme chemistry on sequences
    rather than on metabolite graphs.

    '