Robustness and parameter geography in post-translational modification systems.

Biological systems are acknowledged to be robust to perturbations but a rigorous understanding of this has been elusive. In a mathematical model, perturbations often exert their effect through parameters, so sizes and shapes of parametric regions offer an integrated global estimate of robustness. Here, we explore this "parameter geography" for bistability in post-translational modification (PTM) systems. We use the previously developed "linear framework" for timescale separation to describe the steady-states of a two-site PTM system as the solutions of two polynomial equations in two variables, with eight non-dimensional parameters. Importantly, this approach allows us to accommodate enzyme mechanisms of arbitrary complexity beyond the conventional Michaelis-Menten scheme, which unrealistically forbids product rebinding. We further use the numerical algebraic geometry tools Bertini, Paramotopy, and alphaCertified to statistically assess the solutions to these equations at ∼109 parameter points in total. Subject to sampling limitations, we find no bistability when substrate amount is below a threshold relative to enzyme amounts. As substrate increases, the bistable region acquires 8-dimensional volume which increases in an apparently monotonic and sigmoidal manner towards saturation. The region remains connected but not convex, albeit with a high visibility ratio. Surprisingly, the saturating bistable region occupies a much smaller proportion of the sampling domain under mechanistic assumptions more realistic than the Michaelis-Menten scheme. We find that bistability is compromised by product rebinding and that unrealistic assumptions on enzyme mechanisms have obscured its parametric rarity. The apparent monotonic increase in volume of the bistable region remains perplexing because the region itself does not grow monotonically: parameter points can move back and forth between monostability and bistability. We suggest mathematical conjectures and questions arising from these findings. Advances in theory and software now permit insights into parameter geography to be uncovered by high-dimensional, data-centric analysis.

Identifiability and numerical algebraic geometry.

A common problem when analyzing models, such as mathematical modeling of a biological process, is to determine if the unknown parameters of the model can be determined from given input-output data. Identifiable models are models such that the unknown parameters can be determined to have a finite number of values given input-output data. The total number of such values over the complex numbers is called the identifiability degree of the model. Unidentifiable models are models such that the unknown parameters can have an infinite number of values given input-output data. For unidentifiable models, a set of identifiable functions of the parameters are sought so that the model can be reparametrized in terms of these functions yielding an identifiable model. In this work, we use numerical algebraic geometry to determine if a model given by polynomial or rational ordinary differential equations is identifiable or unidentifiable. For identifiable models, we present a novel approach to compute the identifiability degree. For unidentifiable models, we present a novel numerical differential algebra technique aimed at computing a set of algebraically independent identifiable functions. Several examples are used to demonstrate the new techniques.

Numerical algebraic geometry for model selection and its application to the life sciences.

Researchers working with mathematical models are often confronted by the related problems of parameter estimation, model validation and model selection. These are all optimization problems, well known to be challenging due to nonlinearity, non-convexity and multiple local optima. Furthermore, the challenges are compounded when only partial data are available. Here, we consider polynomial models (e.g. mass-action chemical reaction networks at steady state) and describe a framework for their analysis based on optimization using numerical algebraic geometry. Specifically, we use probability-one polynomial homotopy continuation methods to compute all critical points of the objective function, then filter to recover the global optima. Our approach exploits the geometrical structures relating models and data, and we demonstrate its utility on examples from cell signalling, synthetic biology and epidemiology.