Tunable kinetic proofreading in a model with molecular frustration

In complex systems, feedback loops can build intricate emergent phenomena, so that a description of the whole system cannot be easily derived from the properties of the individual parts. Here we propose that inter-molecular frustration mechanisms can provide non trivial feedback loops which can develop nontrivial specificity amplification. We show that this mechanism can be seen as a more general form of a kinetic proofreading mechanism, with an interesting new property, namely the ability to tune the specificity amplification by changing the reactants concentrations. This contrasts with the classical kinetic proofreading mechanism in which specificity is a function of only the reaction rate constants involved in a chemical pathway. These results are also interesting because they show that a wide class of frustration models exists that share the same underlining kinetic proofreading mechanisms, with even richer properties. These models can find applications in different areas such as evolutionary biology, immunology and biochemistry

Systems Modeling of Calcium Homeostasis and Mobilization in Platelets Mediated by Ip3 and Store-Operated Calcium Entry

Platelet aggregation is one of the body\u27s first responses to vascular damage to prevent blood loss; upon injury to the endothelium platelets react to the exposed extracellular matrix and undergo a host of intracellular biochemical changes enabling them to activate and form a plug at the site of injury. Internally, platelets respond to their environment by exhibiting a sharp rise in cytosolic calcium that triggers a series of chemical and morphological changes which are critical to platelet activation and subsequent clot propagation. This thesis develops a mechanistic, computational model of platelet calcium regulation using coupled sets of ordinary differential equations. This thesis extends previous work modeling calcium release mediated by inositol 1,4,5-trisphosphate (IP3) to engineer what is the first, to date, complete model of store-operated calcium entry (SOCE) integrated into a systems model for calcium signaling. SOCE is a ubiquitous extracellular calcium entry pathway which is activated by calcium store depletion, is seen in many cells types and is yet to be fully understood. Our model for SOCE regulation consists of diffusion-limited dimerization of the calcium sensor STIM1, followed by fast, cytosolic calcium-dependent association of STIM1 dimers with Orai1 channels in the plasma membrane resulting in graded store-operated channel activation. Appropriate model resting states were characterized using a dense Monte Carlo technique on an initial condition sampling space constrained by available data on species concentrations and protein copy numbers. From this set of resting configurations, following application of physiologic IP3 stimuli, we selected for resting states exhibiting calcium dynamics that are in agreement with experimental data. We also selected for states presenting significant SOCE current based on differences in cytosolic calcium between simulations run with and without extracellular calcium. Low resting levels of IP3 are required for system robustness and for simultaneous appropriate dynamic response to physiologic agonists. Platelets require a resting electrical potential across the membrane surrounding the calcium stores of greater than -70 mV in order to exhibit significant agonist-induced calcium release

Exploration of cellular reaction systems

We discuss and review different ways to map cellular components and their temporal interaction with other such components to different non-spatially explicit mathematical models. The essential choices made in the literature are between discrete and continuous state spaces, between rule and event-based state updates and between deterministic and stochastic series of such updates. The temporal modelling of cellular regulatory networks (dynamic network theory) is compared with static network approaches in two first introductory sections on general network modelling. We concentrate next on deterministic rate-based dynamic regulatory networks and their derivation. In the derivation, we include methods from multiscale analysis and also look at structured large particles, here called macromolecular machines. It is clear that mass-action systems and their derivatives, i.e. networks based on enzyme kinetics, play the most dominant role in the literature. The tools to analyse cellular reaction networks are without doubt most complete for mass-action systems. We devote a long section at the end of the review to make a comprehensive review of related tools and mathematical methods. The emphasis is to show how cellular reaction networks can be analysed with the help of different associated graphs and the dissection into modules, i.e. sub-networks