(308c) Multi Scale Product Design From Enzyme Design to Bio Network Control

An efficient product design involves modeling and optimization across length and time scales. This multi scale product design has become widespread in biological systems. In this talk we present a case study of our group's work in multi scale design of biochemical reaction networks. DNA amplification or the Polymerase Chain Reactions (PCR) is the workhorse of nearly every modern molecular biology laboratory, as well as the burgeoning discipline of personalized medicine. Though PCR is simple, this method is often fraught with difficulties that can decrease the cycle efficiency or result in competitive amplification of undesired side products. To date, nearly all approaches to PCR optimization have been based on either heuristic experimental sampling of reaction conditions or calculation of the effects of changes in reaction mixture composition on thermodynamic parameters. By contrast, the engineering discipline of control theory can automatically derive prescriptions for the optimal temperature cycling protocols of a PCR reaction, if a suitable kinetic model exists. We have developed the first sequence and temperature dependent kinetic model for PCR reactions, validating this model through comparison to experimental data. Using this kinetic model we  have analyzed the controllability of PCR and developed a control strategy to maximize the DNA amplification efficiency. Further, we have formulated and solved a large scale constrained dynamic optimization problem and derive the optimal temperature profile that maximizes the amplification of a given target DNA sequence and reduces the overall reaction time. This bionetwork control problem motivates the formulation of DNA oligonucleotide design and polymerase enzyme design objectives. By solving these molecular design problems, we can further improve the amplification selectivity and efficiency. The output of the multi scale product design methodology is a temperature cycling protocol and reaction mixture composition that is tailored for the amplification of any desired DNA target.