The korAB operon in RK2 plasmids is a beautiful natural example of a negatively and cooperatively self-regulating operon. It\r\nhas been particularly well characterized both experimentally and with mathematical models. We have carried out a detailed\r\ninvestigation of the role of the regulatory mechanism using a biologically grounded mechanistic multi-scale stochastic\r\nmodel that includes plasmid gene regulation and replication in the context of host growth and cell division. We use the\r\nmodel to compare four hypotheses for the action of the regulatory mechanism: increased robustness to extrinsic factors,\r\ndecreased protein fluctuations, faster response-time of the operon and reduced host burden through improved efficiency of\r\nprotein production. We find that the strongest impact of all elements of the regulatory architecture is on improving the\r\nefficiency of protein synthesis by reduction in the number of mRNA molecules needed to be produced, leading to a greater\r\nthan ten-fold reduction in host energy required to express these plasmid proteins. A smaller but still significant role is seen\r\nfor speeding response times, but this is not materially improved by the cooperativity. The self-regulating mechanisms have\r\nthe least impact on protein fluctuations and robustness. While reduction of host burden is evident in a plasmid context,\r\nnegative self-regulation is a widely seen motif for chromosomal genes. We propose that an important evolutionary driver\r\nfor negatively self-regulated genes is to improve the efficiency of protein synthesis.
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