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:– 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

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

Main features of the proposal

1. Species are constructed of molecules, molecules – of components.

2. Component = binding site = state variable3. Attributes, variables, stoichiometry = properties

of a component4. Species configuration space is defined by rules

later on, not during molecules declarations.5. Concentrations (all numerics!) are declared

separately from species declaration.

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. Y-P

Shc

Ys-P

Grb2SosYg-U

Ys-U

Yg-P

Grb2Y binding site

UP

Shc

EGF

EGF binding domain E

Grb2 binding site Yg

Shc binding site Ys

EGFR

UP

EGFR binding domain R

UP

SH2

SH3-2

Grb2

Sos

EGFRbinding SH2site

Reaction is a graph rewriting consistent with chemistry

Ys-P

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

Ys-U

Yg-P

Ys-P

Yg-P

Ys-U

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

• Mapping ρ: Rρ -> Pρ preserves, adds and removes molecular entity graphs as units.

Pattern graphs and chemical species selected by patterns

Y-P

Shc

Ys-P

Grb2

Sos

Yg-U

Ys-U

Yg-P

Ys-PYs-P

Yg-P Yg-P

Ys-P

Yg-UY-U

ShcYs-PYg-P

Y-P

ShcYs-P

Grb2 Yg-P

Ys-P

Yg-U

Ys-P

Ys-U

Yg-P

Yg-P

Ys-P

Ys-U

Yg-P

Yg-P

Ys-P

Yg-P

Ys-P

Ys-P

Yg-P

Yg-P

Sos

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.

Ys-P

Yg-P

Ys-P

Yg-P

General XML/SBML structure

SBML L1-L2

UnitsCompartmentsParametersSpeciesReactions Reactants speciesReference Products speciesReference KineticLaw

SBML L3-RBM

Species + components + physicalEntities + bondsReactions Reactants + speciesTemplate Products +? speciesTemplate +? ReactionTemplate

Graph XML

Graph Nodes Edges NodeReferences Transformation RHS GraphReference LHS GraphReference Map NodeToNode EgdeToEdge

Introduction to BioNetGen Language (BNGL)A

b

Y

B

A(b) B(a,Y~U~P,location~Cyt~Nuc)

a

A(b) + B(a) -> A(b!1).B(a!1) p

B(Y~P) -> B(Y~U) da bond between two components

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()

Molecules

Patterns

Reaction rules

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>

component: b-siteid: acompartment: extracellular

component: p-siteid: bcompartment: intracellular

component: p-siteid: gcompartment: intracellular

physicalEntityid: Rstates: u,fcompartment: membrane

Species R(a!1,b~p!2,g~u).L(Fc!1,Fc).Lyn(SH2!2)

id: betastate: p

id: gammastate: u

Lyn2

bondid: 2

1

<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>

speciesTemplate

R(a!1).L(Fc!1,Fc) R(a,g~p!?)

<speciesTemplate id="T_L_monomer"> <listOfPhysicalEntitiesIncluded> …. <listOfComponentInstances> …. …

<listOfPhysicalEntitiesIncluded>

<listOfBonds></speciesTemplate>

id: i1Fccomponent: Fcconnectivity: bound

speciesType: T_lig_monomer

id: ialphacomponent: alphaconnectivity: bound

id: i2Fccomponent: Fcconnectivity: unbound

physicalEntityIncluded: FceRI

physicalEntityIncluded: Lig

1bondid: 1type: external

component: b-siteid: aconnectivity: unbound

component: p-siteid: gcomponentValue: p

speciesTypestate: u

SpeciesPattern: P_lig_bound_once

speciesTypeIncludedInstance: Fcid: i1FcextBonds: 1bondReference: 1

speciesTypeInstance: Ligid: iLig

speciesTypeIncludedInstance: Fcid: i2FcextBonds: 0 id: gamma

state: u

id: betastate: p

Lyn

FceRI

1

SpeciesPattern: P_lig_bound_one_or_more



SpeciesPattern: P_ligand_bound_two_times




not specified - canhave as many bondsas allowed bymaxExternalBonds

1 1

2

FceRI

FceRI

1

FceRI

1

FceRI

2

FceRI

1

FceRI

2

Lyn3

id: gammastate: u

id: betastate: p

id: gammastate: u

id: betastate: p

id: gammastate: u

id: gammastate: u

id: betastate: p

id: gammastate: u

id: betastate: p

id: betastate: p

id: gammastate: u

id: betastate: p

1a Species: S_lig_bound_once1b

2a

1c

2b 2c

3a 3b Species

SpeciesSpecies

Species

1

Reactions and reaction rules

Option 1:

<reaction>

<listOfReactants>

<speciesTemplate id=“R"/>

<speciesReference species="L"/>

</listOfReactants>

<listOfProducts>

<speciesTemplate id=“R-L"/>

</listOfProrducts>

</reactionRule>

Option 2:

<reactionRule>

<listOfReactants>

<speciesTemplate id="T_monomer"/>

<speciesReference species="T_free_L"/>

</listOfReactants>

<reactionTemplate>

<SpeciesTemplateChange>

<bond …>

<kineticLaw>

……

</kineticLaw>

</speciesTemplateChange>

</reactionTemplate>

</reactionRule>

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>


id: iacomponenet: aconnectivity: bound



1bondid: 1




Reactant: speciesType T_monomerphysicalEntityIncluded: R

Reactant: speciesType T_free_ligandphysicalEntityIncluded: L

Product: speciesType T_L_monomer


R(a) + L(Fc,Fc) -> R(a!1).L(Fc!1,Fc)

ReactionRule specification: chemistry-based approach

<reaction>

<listOfReactants>

<speciesTemplate id=“R">

…

</speciesTemplate>

<speciesTempalte id="L"/>

…

</speciesTemplate>

</listOfReactants>

<reactionTemplate> <physicalEntitiesReplacements> <ExternalBondsReplacements>

</reactionTemplate>

</reaction>

Ys-P

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

Ys-U

Yg-P

Ys-P

Yg-P

Ys-U

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

Ys-P

Yg-P

A

a

B

a

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.

Reaction or ReactionRule

R(a) + L(Fc,Fc) -> R(a!1).L(Fc!1,Fc)

<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>





1bondid: 1




Reactant: speciesType T_monomerphysicalEntityIncluded: R

Reactant: speciesType T_free_ligandphysicalEntityIncluded: L

Product: speciesType T_L_monomer


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>

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

<speciesType id="Lig">

<listOfSpeciesTypesIncluded>

<speciesTypeIncluded id="Fc" speciesType="b-site" multiplicity="2“>

</listOfSpeciesTypesIncluded>

</speciesType>

speciesTypeIncluded: b-siteid: Fcmultitplicity:2compartment: extracellular

speciesTypeclass: ”component”id: p-sitestates: u,p

speciesTypeclass: physicalEntityid: Lig

speciesTypeclass: ”component”id: b-site

speciesType

speciesTypeIncluded

<speciesType id="p-site" defaultStateValue=“u”> <listOfSpeciesTypeStates>

<speciesTypeState value="u" name="unphosphorylated"/><speciesTypeState value="p" name="phosphorylated"/

</listOfSpeciesTypeStates></speciesType>

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>





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>





<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>

BondsspeciesType: R speciesTypeIncluded: b-site

id: amaxInternalBonds:1

speciesTypeIncluded: p-siteid: bmaxInternalBonds:2

bondtype: internalid: 1

id : SId {use="optional"} name : string {use="optional"} speciesTypeInstance: speciesType[0..*]compartment: Sid {use="optional"}

speciesTypeInstanceid : 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"}

speciesTemplate

Documents

Needs to be described: