Dominique Lauzon and Alexis Vallée-Berrill
Credit: Amélie Philibert, University of Montreal
By linking molecules together, scientists at the University of Montreal believe they have uncovered how molecular systems evolved to create complex self-regulation at the origin of life.
Their findings, published today in the European journal Angewandte Chemie, promise to provide chemists and nanotechnologists with a simple strategy to create the next generation of dynamic nanosystems.
Life on Earth is sustained by millions of different tiny nanostructures, or nanomachines, that have evolved over millions of years, explained Alexis Vallée-Berrill, professor at UdeM and principal investigator of the study. do.
These structures are often less than 10,000 times the diameter of a human hair and are usually composed of proteins or nucleic acids. Some are made from a single component or piece (often a linear polymer that folds into a specific structure), but most are made from multiple components that spontaneously assemble to form large, dynamic assemblies. is made using.
response to stimulus
“These molecular assemblies are highly dynamic, activating or deactivating in precise response to various stimuli such as changes in temperature, oxygen, and nutrients,” Vallee-Berrill said.
“Like a car, which must fire up, release the brakes, change gears, and turn on the gas in order to move forward, molecular systems use The various nanomachines must be activated or deactivated in sequence.”
The researchers asked fundamental questions about how dynamic molecular assemblies are created, programmed, and fine-tuned to sustain life.
They discovered that many biological assemblies randomly connect interacting molecules (e.g., proteins or nucleic acids such as DNA or RNA) with linkers that act like “connectors” between each part. This means that it is likely to be formed by
“Because these biomolecular assemblies play a critical role in enabling organisms to respond to their environment, we believe that the nature of the connections between attached components also contributes to the evolution of their dynamic responses. “We hypothesized that this might be the case,” said Holder’s Vallée-Berrill. Canada Research Chair in Biotechnology and Bionanotechnology.
Investigate the impact of connectivity
To explore this question, Dominique Lauzon, a PhD student at the time of the study, decided to synthesize and combine dozens of DNA-interacting molecules and investigate the effect of connectivity on the dynamics of the assembly. .
“The chemistry of nucleic acids, such as DNA, is programmable and easy to use, making them useful molecules for studying fundamental questions about the evolution of biomolecules,” said Lauzon, lead author of the study. “Furthermore, nucleic acids are also thought to be the origin molecules of life on Earth.”
Lauzon and Vallée-Bélisle found that simple changes in the length of the “linker” between interacting molecules lead to large changes in their assembly dynamics. For example, certain assemblages showed high sensitivity to stimulus changes, while other assemblages lacked such sensitivity or required much larger stimulus changes to promote aggregation. Sometimes I even did it. Even more surprising, some linkers even generate new complex regulatory functions, such as autoinhibitory properties, with stimulation promoting both their assembly and disassembly. All these different reaction behaviors are also commonly observed in natural “living” nanomachines.
Using experiments and formulas, the researchers were also able to explain why such simple changes in linker length are so efficient at altering the dynamics of molecular assembly. “Linkers that create the most stable assemblies also create the most sensitive activation mechanisms, whereas linkers that create less stable assemblies have less sensitive activation mechanisms, to the point of introducing self-inhibition.” ,” Lauzon explained.
sensing is important
The ability to accurately sense molecular signals is important not only for biological assemblies but also for the development of nanotechnology that relies on the detection and integration of molecular information.
The researchers therefore believe that their findings serve as a basis for creating more programmable nanomachines or nanosystems with optimally controlled activity, for example by simply joining interacting molecules with different linkers. We believe that it may also provide a framework. Such molecular assemblies have already found applications in biosensing and drug delivery.
In addition to providing a facile design strategy to create the next generation of self-regulating nanosystems, the scientists’ findings shed light on how natural biomolecular assemblies acquire their optimal dynamics. was also revealed.
“One of the well-known molecular evolution strategies of living organisms is gene fusion, in which DNA encoding two interacting protein domains is randomly fused together,” Vallée-Bélisle said. “Our findings also demonstrate how simple changes in linker length between fusion proteins can efficiently generate biological assemblies that exhibit different dynamics, making some more suitable than others to provide an advantage to the organism. It provides the basic understanding needed to understand how it was created.