On a table lies a handful of coins of the same denomination but different minting. Weigh the whole handful at once and you learn only the average weight, not the story of each coin. Much the same way, mass spectrometry with hydrogen-deuterium exchange (HDX/MS) long looked at DNA quadruplexes, unusual structures made of four guanine strands that stack like a pile of pancakes with potassium ions between them. In solution they form a mixture of conformations with the same mass, and the method produced averaged exchange kinetics, as if all the coins were identical.
The authors of the new study added a third dimension: ion mobility (IMS). This method forces ions to fly through a tube filled with helium under the influence of an electric field. The flight time depends on the shape and charge of the ion: a compact ball will arrive faster than an unfolded chain, even if their masses are equal. Now each conformation gets its own "address" based on drift time, and the exchange rate can be measured for each one separately.
For the telomeric sequence 23TAG, which forms two hybrid conformations, they managed to separate them and measure individual rates. It turned out that one form (hybrid-2) unfolds three times faster than the other (hybrid-1): 1.76 versus 0.57 per minute. This difference is not about local fluctuations but about different rates of complete unfolding of the structure, as if one coin bent more easily than another.
The third scenario showed that not all differences in shape matter: for a monomorphic quadruplex, two peaks were observed in the drift time distribution, but the exchange rates for them were identical. This means the differences arose already in the gas phase, not in solution. Such a check helps keep an artifact from being mistaken for real biology.
Now researchers have a tool that sorts molecular coins not only by weight but also by shape and by exchange rate. This makes it possible to peer into the dynamics of each DNA conformation, which matters for developing drugs that target quadruplexes and for testing the stability of therapeutic oligonucleotides. The handful of coins can finally be sorted one by one.
Guanine quadruplexes can form structures reminiscent of a stack of pancakes: flat guanine tetrads pile on top of one another, and potassium ions sit between them like filling.
The idea of separating molecules by shape in the gas phase is reminiscent of a fictional "sorter" from a Philip K. Dick story, where objects are classified by nonobvious features. Only here, instead of a fantastic device, there is a drift tube filled with helium.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.