Systems Modelling Tool
Allosteric Network Compiler (ANC)
by Ollivier JF, Shahrezaei V. and Swain PS
Method: Rule-based, with integrated free energy-based constraints
Efficiency: Combinatorial complexity is minimised by employing a few (2 or 3) intensive parameters.
Characteristics:
The rule-based system built on Monod-Wyman-Changeux paradigm of allostery of two states (T:tense or R:relaxed), the system employs: a regulatory factor gamma (Γ) which gives fold-changes of equilibrium constant; and one or more phi-values which give the effect of the ligands on forward and reverse rates in allosteric transition.
The model comprises a set of modular structures and interaction rules.
Each structure has a set of named components. There are two types of components: 1) hierarchical components that can either be compositing/constituting higher structures (domains, subunits) or as allosteric it undergoes conformational transition according to two-states model; and 2) the three interaction sites (catalytic, covalent-modification, ligand-binding).
Rules specify the interactions between the sites, and also how a conformational state or a modification state of the protein affects the strength of the associations. Rule thereby gives dissociation rates according to the nature of interactions.
Considering an allosteric protein as a modular, a binding modifier is an input for the output: the lengths of time at which the receptor component spent in each conformation when the allosteric transition is at equilibrium.
Free energy-based constraints is integrated as thermodynamic framework, to determine the collective effects of multiple modifiers on the conformational equilibrium. All modifiers are regarded to interact independently with each conformational state of the protein body, contribute independently to the free energy, and affects kinetic rates independently.
After a series of iterations, a biochemical reaction network is obtained; that is
exportable by Facile to perform deterministic or stochastic simulation in maths softwares such as MATLAB and Mathematica.
For GPCRs
Cubic ternary complex model is implemented with a single allosteric component and receptor with two conformational states, regardless of cooperativity in ligand binding, because introducing cooperativity factors into the model increases combinatory complexity. For a better efficiency, a sequential allosteric model termed quartic ternary complex model was introduced. The quartic model comprises two coupled allosteric components: an extracellular domain (ED) which binds to a ligand existing in transition between low and high-affinity states (s and t), and an intracellular domain (ID) which associates with G-protein and in transition between active and inactive states (i and a). The two components are linked, and each domain can be a modifier to the other by associations which are parameterised by the factor Γ and phi values. No parameter in the model is for a ligand--G-protein pairing.
The quartic model has 11 parameters including 3 intensive ones.
The quartic model is modular and is expandable to incorporate additional interactions such as oligomerisation.
However, the performance may deteriorate as the compiled network increase in size.
No comments:
Post a Comment