Protein interactions are a key building block of biological networks controlling the flow of information, energy, and metabolites. The engineering of multi-protein systems is, therefore, an important, but a currently underexplored, area of synthetic biology. I outline a protein systems engineering framework that uses protein-protein interactions as its basic building block. The systematic combination of protein docking and molecular dynamics simulations revealed considerable complexity already in the simple binding of two proteins. Nevertheless, this complexity was tamed experimentally through the recombination of flexibly connected interaction modules. Following this strategy, carefully chosen or computationally designed helper modules amplified and "normalized" the real-time detection of protein binding events (hiFRET). This now opens the door to the construction of genuine protein computation circuits with various applications from cheap CRISPR-based DNA biosensors to smart biologicals for cell therapy.
Currently, such bioengineering is held back a large gap between our very limited capacity to experimentally characterize biological building blocks or actual designs, on the one hand, and a wealth of candidate parts and hypothetical designs suggested by bioinformatic analysis or modeling, on the other hand. I propose a novel research platform that bridges this gap by integrating robotic DNA assembly with cell-free expression, microfluidics, and advanced interaction sensors. This platform will not only enable rapid protein circuit engineering but will also be geared towards metagenome-scale characterization of enzymatic activities as well as the combinatorial assembly of biosynthesis pathways for drug screening or metabolic prototyping.
Raik Grünberg is a synthetic biologist with roots in computational biophysics and experimental protein design. After studying Biochemistry at the University of Leipzig (Germany), Raik performed his Ph.D. in biophysics at the EMBL in Heidelberg (Germany) and the Pasteur Institute in Paris on the automated modeling and atomic-detail simulation of protein complexes. This resulted in a widely quoted mechanistic model of protein-protein binding and pushed the boundary of what was considered technically feasible in protein-protein docking. As a postdoc at the Center for Genomic Regulation (CRG) in Barcelona, he entered the emerging field of synthetic biology and set the groundwork for the experimental design of synthetic protein systems. He then took up a research associate position at the University of Montreal (Canada) where he started up a new protein synthetic biology lab and sub-group. He is currently offering consulting services on the robotic automation of molecular and synthetic biology workflows and is a visiting researcher at KAUST.
Raik has received a Boehringer Ingelheim Foundation Ph.D. fellowship and Marie Curie as well as Human Frontier Science Program (HFSP) postdoctoral fellowship awards. Raik is co-founder and editor of the Synthetic Biology Open Language (SBOL), an international effort connecting key industry and academic players to set standards for an emerging tool stack of automated biological design. Typical for his role at the interface of computational and experimental bioengineering, he is also serving as the chair of the iGEM software track.