From quadruplex to helix and back: Meta-stable states can move through a cycle of conformational changes

Strand displacement cycles can be driven by sequential addition of short oligonucleotide sequences. Successive inter- and intra-molecular interactions based on the rules of Watson–Crick base pairing allow us to design self-assembling molecular systems with predictable folding pathways and conformational changes. Here we present a particular strand displacement cycle that starts from a tethered quadruplex-forming sequence from the human telomere repeat (T2AG3)4 that forms a G-quartet within a stem-loop structure. Adding an almost matching single strand converts the four-stranded section into a defective double helix. This is the first step of the cycle. The subsequent addition of a “fuel strand” removes the single strand from the loop sequence in favor of a perfect double helix. This displacement frees the hairpin-loop to go back to its initial state. Analysis of this cycle, that resembles an enzyme–substrate pathway as far as the initial state will be regained at the end of the cycle, advances our understanding of the interchanges between meta-stable states that underlie some fundamental steps in molecular biology, and allow for the construction of nano-molecular machines.