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Needs to be described:

Needs to be described:. Objects Have multiple states Consist of other objects, that may have multiple states May be connected with each other via different bonds Located in multiple compartments, with two objects within the third can be in three different compartments. Rules:

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Needs to be described:

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  1. Needs to be described: • Objects • Have multiple states • Consist of other objects, that may have multiple states • May be connected with each other via different bonds • Located in multiple compartments, with two objects within the third can be in three different compartments. • Rules: • Select sets of objects with common properties • Transform sets of objects into another sets of objects, generating reactions • Add kinetic laws to reactions • Representational issues (compatible with SBGN) • Rules application: • Stochastic application • Rules priority, score, confidence • Restrictions on the number of applications

  2. Two approaches to define SBML • Graph-based approach with the fixed hierarchy (BNG, Simmune, StochSim, Moleculizer, MIM) • Graph-based approach with an arbitrary level of hierarchy (A Finney) • Start with the simplest

  3. Main features of the proposal • Species are constructed of molecules, molecules – of components. • Component = binding site = state variable • Attributes, variables, stoichiometry = properties of a component • Species configuration space is defined by rules later on, not during molecules declarations. • Concentrations (all numerics!) are declared separately from species declaration.

  4. Molecular Entities and Chemical Species graphs • A Chemical Species Graph C is a fully defined molecular entity or a set of molecular entities. • Any and all variable attributes taking specific values.

  5. Reaction is a graph rewriting consistent with chemistry • Mapping ρ: Rρ -> Pρpreserves, adds and removes molecular entity graphs as units.

  6. Pattern graphs and chemical species selected by patterns

  7. Graph transformation on patterns • Find reactant chemical species C matched by RP • Replace image of RP in C by PP via f. • Preserve edges, vertices and attributes of vertices in C not specified in RP. • Remove dangling edges.

  8. General XML/SBML structure Graph XML Graph Nodes Edges NodeReferences Transformation RHS GraphReference LHS GraphReference Map NodeToNode EgdeToEdge SBML L3-RBM Species + components + physicalEntities + bonds Reactions Reactants + speciesTemplate Products +? speciesTemplate +? ReactionTemplate SBML L1-L2 Units CompartmentsParameters Species Reactions Reactants speciesReference Products speciesReference KineticLaw

  9. Introduction to BioNetGen Language (BNGL) A B b a Y B(a,Y~U~P,location~Cyt~Nuc) A(b) Molecules B_tot B() B_unbound B(a) B_bound B(a!+) B_phospho_all B(Y~P!?) B_phospho_unbound B(Y~P) B_phospho_bound B(Y~P!+) A_B_complex A().B() Patterns A(b) + B(a) -> A(b!1).B(a!1) p B(Y~P) -> B(Y~U) d Reaction rules a bond between two components

  10. Components and physical entities R(a,b~u~p,g~u~p) <physicalEntity id=“R“ compartment=“m"/> <listOfStates> <state value="u“ name=“unfolded"/> <state value=“f“ name=“folded"/> </listOfStates> <listOfComponents> <component id="a" componentType="b-site"/> <component id="b" componentType="p-site"> <listOfComponentTypeStates> <componentTypeState value="u" name="unphosphor"/> <componentTypeState value="p" name="phosphor"/> </listOfComponentTypeStates> </component> <component id="g" componentType="p-site" compartment="ic"/> </listOfComponents> </physicalEntity>

  11. Species R(a!1,b~p!2,g~u).L(Fc!1,Fc).Lyn(SH2!2) <species id="S_lig_monomer_Lyn "> <listOfPhysicalEntityInstances> <physicalEntityInstance physicalEntity="L" id="iL"> <listOfComponentInstances> <componentInstance id="i1Fc" component="Fc"/> <listOfBondReferences> <bondReference bond="1"/> </listOfBondReferences> </componentInstance> <componentInstance id="i2Fc" component="Fc"/> </listOfComponentInstances> </physicalEntityInstance> ….. </listOfPhysicalEntityInstances> <listOfBonds> <bond id="1" type="external"/> <bond id="2" type="external"/> </listOfBonds> </species>

  12. speciesTemplateR(a!1).L(Fc!1,Fc)R(a,g~p!?) <speciesTemplate id="T_L_monomer"> <listOfPhysicalEntitiesIncluded> …. <listOfComponentInstances> …. … <listOfPhysicalEntitiesIncluded> <listOfBonds> </speciesTemplate>

  13. Reactions and reaction rules Option 2: <reactionRule> <listOfReactants> <speciesTemplate id="T_monomer"/> <speciesReference species="T_free_L"/> </listOfReactants> <reactionTemplate> <SpeciesTemplateChange> <bond …> <kineticLaw> …… </kineticLaw> </speciesTemplateChange> </reactionTemplate> </reactionRule> Option 1: <reaction> <listOfReactants> <speciesTemplate id=“R"/> <speciesReference species="L"/> </listOfReactants> <listOfProducts> <speciesTemplate id=“R-L"/> </listOfProrducts> </reactionRule>

  14. ReactionRule specification: graph-based approach <reaction> <listOfReactants> <speciesTemplate id=“R"> …… </speciesTemplate> <speciesTemplate id=“L”/> …… </speciesTemplate> </listOfReactants> <listOfProducts> <speciesTemplate id=“R-L"> …… </speciesTemplate> </listOfProrducts> <kineticLaw> ….. </kineticLaw> </reaction> R(a) + L(Fc,Fc) -> R(a!1).L(Fc!1,Fc)

  15. ReactionRule specification: chemistry-based approach <reaction> <listOfReactants> <speciesTemplate id=“R"> … </speciesTemplate> <speciesTempalte id="L"/> … </speciesTemplate> </listOfReactants> <reactionTemplate> <physicalEntitiesReplacements> <ExternalBondsReplacements> </reactionTemplate> </reaction>

  16. a a A B How to select A as reactant and transform into B while preserving states of component a? Easy to do operationally, but harder to define using standard semantics of chemical semantics. Need notion of mapping. Challenge: L3M should encompass.

  17. <reaction id="Ligand_bind" reversible="true"> <listOfReactants> <speciesTemplate id="T_monomer"/> <speciesTemplate species="T_free_L"/> </listOfReactants> <reactionTemplate> <SpeciesTemplateChange> <bond …> <kineticLaw> …… </kineticLaw> </speciesTemplateChange> </reactionTemplate> </reactionRule> Reaction or ReactionRule R(a) + L(Fc,Fc) -> R(a!1).L(Fc!1,Fc)

  18. Logic and Range (BioPAX) <physicalEntity id="R" > <listOfComponents> <component id="a"> <listOfStates> <state id="sta1"/> …… <state id="sta6"/> </listOfStates> </component> </listOfComponents> </physicalEntity> <speciesTemplate id="T_R"> <listOfPhysicalEntityInstances> <physicalEntityInstance physicalEntity="R" id="iR"> <listOfComponentInstances> <componentInstance value="ia" component="a" state=“ NOT sta1"/> <componentInstance value="ia" component=“a" state="sta1" OR "sta2"/> <componentInstance value="ia" component=“a" state="[sta3… sta5]"/> </listOfComponentInstances> </physicalEntityInstance> </listOfPhysicalEntityInstances> </speciesTemplate>

  19. Arbitrary level of hierarchy • Why not specify components and physicalEntities as speciesTypes? • Advantage: generality • Problem: does not allowed by current SBML standard • Cost: complexity of connectivity

  20. speciesTypespeciesTypeIncluded <speciesType id="p-site" defaultStateValue=“u”> <listOfSpeciesTypeStates> <speciesTypeState value="u" name="unphosphorylated"/> <speciesTypeState value="p" name="phosphorylated"/ </listOfSpeciesTypeStates> </speciesType> <speciesType id="Lig"> <listOfSpeciesTypesIncluded> <speciesTypeIncluded id="Fc" speciesType="b-site" multiplicity="2“> </listOfSpeciesTypesIncluded> </speciesType>

  21. speciesType id : SId name : string {use="optional"} class: string {"component", "physicalEntity", …} {use="optional"} speciesTypeState: string [0..*] {use="optional"} speciesTypeIncluded: speciesTypeIncluded[0..*] compartment: Sid {use="optional"} <speciesType id="p-site" class="components" name="site_of_phosphorylation“ defaultStateValue=“u”> <listOfSpeciesTypeStates> <speciesTypeState value="u" name="unphosphorylated"/> <speciesTypeState value="p" name="phosphorylated"/ </listOfSpeciesTypeStates> </speciesType>

  22. speciesTypeIncluded Id: SId name : string {use="optional"} multiplicity: int { minInclusive="0" use="optional" default="1"} maxExternalBonds: int { minInclusive="0" use="optional" default="1"} maxInternalBonds: int { minInclusive="0" use="optional" default="0"} compartment: Sid {use="optional"} <speciesType class="physicalEntity" id="Lig"> <listOfSpeciesTypesIncluded> <speciesTypeIncluded id="Fc" speciesType="b-site" multiplicity="2“> </listOfSpeciesTypesIncluded> </speciesType>

  23. Bonds <speciesType class="physicalEntity" id="R"> <listOfSpeciesTypesIncluded> <speciesTypeIncluded id="a" speciesType="b-site" maxInternalBonds ="1"> <listOfBondReferences> <bondReference bond="1"/> </listOfBondReferences> <speciesTypeIncluded/> <speciesTypeIncluded id="b" speciesType="p-site" maxInternalBonds =“1"> <listOfBondReferences> <bondReference bond="1"/> </listOfBondReferences> <speciesTypeIncluded/> </listOfSpeciesTypesIncluded> <listOfBonds> <bond id="1" bondType="internal"/> </listOfBonds> </speciesType>

  24. speciesTemplate id : SId {use="optional"} name : string {use="optional"} speciesTypeInstance: speciesType[0..*] compartment: Sid {use="optional"} speciesTypeInstance id : SId speciesTypeValue: speciesTypeValue {use="optional"} name : string {use="optional"} multiplicity: int { minInclusive="0" use="optional" default="1"} extBonds: int { minInclusive="0" maxInclusive="maxExtBonds" use="optional"} intBonds: int { minInclusive="0" maxInclusive="maxIntBonds" use="optional"}

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