The filamentous bacteriophage of <i>E. coli</i> are important model systems for unraveling the details of DNA replication and membrane protein insertion in prokaryotes, are prominently used as the platform for phage display, and are increasingly finding utility as scaffolds for nanoscale devices from biosensors to batteries. Although long studied, many aspects of phage biology are still poorly understood. As the biotechnological applications of phage particles continue to expand in scope and complexity, a quantitative, holistic understanding of the biological processes and interactions that govern the life cycle of the phage will foster the creation of new platforms with rationally designed control elements that are more amenable to engineering. We have constructed a genetically-structured, experimentally-based computational simulation of the life cycle of the filamentous bacteriophage M13. Our simulation integrates 50 years of experimental observations to evaluate and expand the system level understanding of M13. Our deterministic chemical kinetic simulation explicitly includes the molecular details of phage DNA replication, mRNA transcription, protein translation and phage particle assembly, as well as the competing protein-protein and protein-nucleic acid interactions that control the timing and extent of phage production. Our simulation provides a quantitative description of phage biology and highlights gaps in the present understanding of the M13 life cycle. Many aspects of M13 biology are faithfully reproduced, including the production levels and timing of the shift between replicative form and preassembly complex DNA, quantities of phage mRNA and proteins, and the time course of assembly and release of progeny phage. The simulation was employed to evaluate the importance of various inherent and dynamic elements in the regulation of the phage life cycle. We describe the relative importance of phage genome structure, promoter and ribosome binding site strengths, and dynamic protein and mRNA levels and binding interactions in controlling the initial phage infection. The simulation reveals potentially important, but largely overlooked, control elements in the phage life cycle. Understanding the subtleties of regulation will be important for maximally exploiting the phage for biotechnological applications. We expect that our simulation will help prioritize future biochemical experiments and be useful for designing new synthetic phage-like systems

Computational life cycle modeling of M13 bacteriophage: Toward rational engineering of a biotechnologically-important scaffold

249th National Meeting (2015)

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