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Regulatory RNAs transiently morph into non-native high-energy "excited" conformational states that remodel the native ground state secondary structure needed for function. For two HIV-1 regulatory RNAs, we show that stabilizing excited states using point substitution mutations leads to potent conformation-dependent inhibition of RNA cellular activity to a degree that correlates with the extent of excited state stabilization. Stabilizing non-native excited states potentially provides a generaldoi:10.1101/634576 fatcat:ps6lailprze47efecn5lvj7r2y