In there any speed-accuracy tradeoff for various non-cognate species in nucleotide substrate incorporation and selection of RNA polymerase elongation?*

Here a kinetic framework was firstly constructed to illustrate fidelity control or stepwise nucleotide substrate selectivity in an RNA polymerase transcription elongation cycle with multiple kinetic checkpoints. In earlier literatures, an efficiency-accuracy tradeoff was suggested as the system operates close to its maximal accuracy (exp[Emax)/kBT]) when the enzyme efficiency (kmax/KM) approaches zero, with Emax the maximum selection energetics accumulated, and kmax and KM the limiting rate and apparent Michaelis-Menten constant. The tradeoff was proposed when system kinetic rates were varied under experimental conditions. Currently, we focus on potential tradeoff between an overall speed of elongation and selection accuracy (error rate) with constant kinetic parameters for cognate substrate. With various non-cognate substrates, multiple kinetic checkpoints are allowed to vary with different distributions of selection energetics. The tradeoff seems to reveal from biochemical data as well as all-atom molecular dynamics simulation results. The left questions include how much the selection energetics are bounded and allocated among the checkpoints. The study can be applied to the template-based synthesis in the central dogma. It connects chemical nonequilibrium kinetics with molecular structural dynamics, and also reveals design principles for non-cognate or drug compounds to interfere with the selection systems for therapeutics.