Abstract: Disclosed are techniques for enhanced nucleic acid detection using blocked or partially blocked crRNAs or target RNAs, and a composition of matter (detection reactions consisting of occluded crRNAs or target RNAs). Here, the mechanism of Cas 13 protein activation in response to RNA structure perturbations was systematically probed using a massively multiplexed screen. It was found that there are two distinct sequence-independent modes by which secondary structure affects Cas13 activity: structure in the protospacer region competes with the crRNA and can be disrupted via a strand-displacement mechanism, while structure in the region 3? to the protospacer has an allosteric inhibitory effect. The kinetic nature of the strand displacement process was leveraged to improve Cas13-based RNA detection and enhance mismatch discrimination by up to 50-fold, enabling sequence-agnostic mutation identification at low (<1%) allele frequencies.