Constrained Brownian dynamics simulations for engineering macromolecular interactions

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Avi Robinson-Mosher, Tamar Shinar, Pamela Silver, Jeffrey Way

Wyss Institute for Biologically Inspired Engineering, United States

The quantitative movement and binding properties of genetically engineered systems of proteins are difficult to predict. Thus, it is difficult to choose parameters such as binding constants and attachment geometries in creating high-level design specifications for a synthetic-biological system. To address this issue, we have developed a constrained Brownian dynamics simulation framework that operates on simplified models of protein systems, with the goal of performing long time scale simulations. The behavior of a simulated protein system is determined by integrating Newton’s equations of motion in time without inertia, with Brownian forces and fluid drag, and subject to constraints on excluded volume, relative positions and protein-protein binding interactions. Proteins are abstracted as rigid spheres, with binding surfaces defined radially within them. Peptide linkers are abstracted as small protein-like spheres with rigid connections. To address whether our framework could generate useful predictions, we simulated the behavior of an engineered fusion protein consisting of two 20kD proteins attached by flexible glycine/serine-type linkers. The two protein elements remained closely associated, as if constrained by a random walk in three dimensions of the peptide linker, as opposed to showing a distribution of distances expected if movement were dominated by Brownian motion of the protein domains only. These specific results have implications for the design of targeted fusion proteins. More broadly, the simulation framework described here can be extended to include more detailed system features such as non-spherical protein shapes, electrostatics, etc., without requiring detailed, computationally expensive specifications. This framework should be useful in predicting behavior of engineered protein systems including binding and dissociation reactions.