Building big molecules bottom-up

April 12, 2022 | Rachel Ehrenberg

Building big molecules bottom-up

Just tossing mortar and bricks together won’t yield a tidy structure, but chemists must often resort to similar measures when building molecules the size of proteins, the workhorses of cells. Now researchers have developed a cleaner strategy for constructing such compounds. By employing one kind of molecule as a template, scientists can string together small biologically important molecules into larger ringed structures with unprecedented precision and no mess, a team reports in the Jan. 6 Nature.

THINK BIG Smooth construction of a supersized ringed molecule ensues when building block molecules (red) have fewer binding sites than the template molecules (blue). M.C. O’Sullivan et al/Nature 2011.

The new technique hits a previously inaccessible sweet spot, yielding hefty molecules that approach the size of proteins, the macromolecules that are the movers and shakers of the cellular world. The method could become a broadly used tool for building big molecular structures, including more templates to build even larger compounds. And because the rings are built from strands of compounds of the same class as the pigment chlorophyll, the large loops may exhibit unusual electrical properties and could help researchers better understand how the pigments that drive photosynthesis harvest light.

“We’d like to think the use would be very general — there’s no reason it shouldn’t be,” says chemist Harry Anderson of the University of Oxford in England, who led the new work. “People often want to make objects that are a particular size and shape.”

While nature is fond of using templates for building specific structures — a single strand of DNA, for example, is the template for the other strand — tools that enable such precision have eluded chemists. 

“It’s difficult to create well-defined architectures. We can’t achieve the same specificity and efficiency that nature routinely does,” says Jonathan Lindsey of North Carolina State University in Raleigh, who was not involved in the research. “This approach is really quite attractive.”

Anderson and his colleagues began with a solution containing their template, starlike rings that had six prongs available for binding. Then they added strands of their bricks: a row of four linked porphyrins, round pigments of the same class as the molecules that make blood red and grass green. The ropey strands of porphyrins wound around the templates like a bike chain looping around a gear. And because of the intentional mismatch in the number of binding sites on the template (six) and the porphyrin strands (four), leftover strands looped around a second template, creating a figure eight. Removing the templates yielded large, perfect 12-porphyrin rings, one of the largest organic molecular rings ever synthesized, the team reports.

Typically, to build such a hefty compound from scratch “you have to go through a very lengthy program with step after step after step,” notes Lindsey.  Yet such compounds are too small to be made with top-down methods such as lithography, where bulk material is pared down.

“There’s a realm that’s been really hard to penetrate — this intermediate dimension that’s been hard to get at with chemistry and hard to get at with lithography,” Lindsey says. “That’s what makes it cool.”