Identification of biomolecule mass transport and binding rate parameters in living cells by inverse modeling

BACKGROUND: Quantification of in-vivo biomolecule mass transport and reaction rate parameters from experimental data obtained by Fluorescence Recovery after Photobleaching (FRAP) is becoming more important. METHODS AND RESULTS: The Osborne-Moré extended version of the Levenberg-Marquardt optimization algorithm was coupled with the experimental data obtained by the Fluorescence Recovery after Photobleaching (FRAP) protocol, and the numerical solution of a set of two partial differential equations governing macromolecule mass transport and reaction in living cells, to inversely estimate optimized values of the molecular diffusion coefficient and binding rate parameters of GFP-tagged glucocorticoid receptor. The results indicate that the FRAP protocol provides enough information to estimate one parameter uniquely using a nonlinear optimization technique. Coupling FRAP experimental data with the inverse modeling strategy, one can also uniquely estimate the individual values of the binding rate coefficients if the molecular diffusion coefficient is known. One can also simultaneously estimate the dissociation rate parameter and molecular diffusion coefficient given the pseudo-association rate parameter is known. However, the protocol provides insufficient information for unique simultaneous estimation of three parameters (diffusion coefficient and binding rate parameters) owing to the high intercorrelation between the molecular diffusion coefficient and pseudo-association rate parameter. Attempts to estimate macromolecule mass transport and binding rate parameters simultaneously from FRAP data result in misleading conclusions regarding concentrations of free macromolecule and bound complex inside the cell, average binding time per vacant site, average time for diffusion of macromolecules from one site to the next, and slow or rapid mobility of biomolecules in cells. CONCLUSION: To obtain unique values for molecular diffusion coefficient and binding rate parameters from FRAP data, we propose conducting two FRAP experiments on the same class of macromolecule and cell. One experiment should be used to measure the molecular diffusion coefficient independently of binding in an effective diffusion regime and the other should be conducted in a reaction dominant or reaction-diffusion regime to quantify binding rate parameters. The method described in this paper is likely to be widely used to estimate in-vivo biomolecule mass transport and binding rate parameters

Model-reduced gradient-based history matching

Gradient-based history matching algorithms can be used to adapt the uncertain parameters in a reservoir model using production data. They require, however, the implementation of an adjoint model to compute the gradients, which is usually an enormous programming effort. We propose a new approach to gradient-based history matching which is based on model reduction, where the original (nonlinear and high-order) forward model is replaced by a linear reduced-order forward model and, consequently, the adjoint of the tangent linear approximation of the original forward model is replaced by the adjoint of a linear reduced-order forward model. The reducedorder model is constructed with the aid of the proper orthogonal decomposition method. Due to the linear character of the reduced model, the corresponding adjoint model is easily obtained. The gradient of the objective function is approximated, and the minimization problem is solved in the reduced space; the procedure is iterated with the updated estimate of the parameters if necessary. The proposed approach is adjointfree and can be used with any reservoir simulator. The method was evaluated for a waterflood reservoir with channelized permeability field. A comparison with an adjoint-based history matching procedure shows that the model-reduced approach gives a comparable quality of history matches and predictions. The computational efficiency of the model-reduced approach is lower than of an adjoint-based approach, but higher than of an approach where the gradients are obtained with simple finite differences.Delft Institute of Applied MathematicsElectrical Engineering, Mathematics and Computer Scienc