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.