Tag: Molecules

Scientists Unveil Groundbreaking Single-Molecule Detection Technique

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The heart of this study is a fiber microcavity. Here, one can see a small concave depression in the surface of an optical fiber. The researchers used a microcavity with two concave mirrors, but this image of a single concave microcavity makes it easier to see the fiber mirror setup. Credit: Photo by Carlos Saavedra / UW–Madison

University of Wisconsin–Madison scientists have developed a new, highly sensitive method to detect and analyze single molecules without using fluorescent labels, potentially transforming research in drug discovery and materials science.

Researchers at the University of Wisconsin–Madison have developed the most sensitive method yet for detecting and profiling a single molecule — unlocking a new tool that holds potential for better understanding how the building blocks of matter interact with each other. The new method could have implications for pursuits as varied as drug discovery and the development of advanced materials.

The technical achievement, detailed in a paper published in the journal Nature, marks a significant advance in the burgeoning field of observing individual molecules without the aid of fluorescent labels. While these labels are useful in many applications, they alter molecules in ways that can obscure how they naturally interact with one another. The new label-free method makes the molecules so easy to detect, it is almost as if they had labels.

“We’re very excited about this,” says Randall Goldsmith, a UW–Madison professor of chemistry who led the work. “Capturing behaviors at the level of single molecules is an amazingly informative way of understanding complex systems, and if you can build new tools that grant better access to that perspective, those tools can be really powerful.”

While researchers can glean useful information from studying materials and biological systems at larger scales, Goldsmith says that observing the behavior of and interactions between individual molecules is important for contextualizing that information, sometimes leading to new insights.

“When you see how nations interact with each other, it all comes down to interactions between individuals,” says Goldsmith. “You wouldn’t even think of understanding how groups of people interact with each other while ignoring how individuals interact with each other.”

The Importance of Single Molecule Observation

Goldsmith has been chasing the allure of single molecules since he was a postdoctoral researcher at Stanford University more than a decade ago. There, he worked under the chemist W.E. Moerner, who received the Nobel Prize in chemistry in 2014 for developing the first method of using light to observe a single molecule.

Since Moerner’s initial success, researchers around the world have devised and refined new ways to observe these tiny bits of matter.

The method that the UW–Madison team developed relies on a device called an optical microresonator, or microcavity. As its name suggests, the microcavity is an extremely tiny space where light can be trapped in both space and time — at least for a few nanoseconds — where it can interact with a molecule. Microcavities are more commonly found in physics or electrical engineering laboratories, not chemistry labs. Goldsmith’s history of combining concepts from disparate scientific fields was recognized in 2022 with a Polymath award from Schmidt Futures.

Microcavities are built from incredibly small mirrors fashioned right on top of a fiber optic cable. These fiber optic mirrors bounce the light back and forth many times very quickly within the microcavity.

Potential Applications and Future Developments

The researchers let molecules tumble into the cavity, let the light pass through it, and can not only detect the molecule’s presence, but also learn information about it, such as how fast it moves through water. This information can be used to determine the molecule’s shape, or conformation.

“Conformation at the molecular level is incredibly important, particularly for thinking about how biomolecules interact with each other,” says Goldsmith. “Let’s say you have a protein and you have some small-molecule drug. You want to see if the protein’s druggable, which is to say, ‘Does the drug have some kind of major interaction with the protein?’ One way you might be able to see that is if it introduces a conformational change.”

There are other ways to do that, but they require large amounts of sample material and time-consuming analyses. With the newly developed microcavity technique, Goldsmith says, “We can potentially build a black-box tool to give us the answer in tens of seconds.”

The team, which included Lisa-Maria Needham, a former postdoctoral researcher who is now a laboratory director at the University of Cambridge, has filed a patent for the device. Goldsmith says the device and methods will now be refined over the next couple of years. In the meantime, he says he and his collaborators are already thinking about the many ways it could be useful.

“We’re excited about many other applications in spectroscopy,” he says. “We hope we can use this as a stepping stone to other ways to learn about molecules.”

Reference: “Label-free detection and profiling of individual solution-phase molecules” by Lisa-Maria Needham, Carlos Saavedra, Julia K. Rasch, Daniel Sole-Barber, Beau S. Schweitzer, Alex J. Fairhall, Cecilia H. Vollbrecht, Sushu Wan, Yulia Podorova, Anders J. Bergsten, Brandon Mehlenbacher, Zhao Zhang, Lukas Tenbrake, Jovanna Saimi, Lucy C. Kneely, Jackson S. Kirkwood, Hannes Pfeifer, Edwin R. Chapman and Randall H. Goldsmith, 8 May 2024, Nature.
DOI: 10.1038/s41586-024-07370-8

This research was primarily funded by the National Institutes of Health (R01GM136981), with resonator construction supported by the Q-NEXT Quantum Center, a U.S. Department of Energy, Office of Science, National Quantum Information Science Research Center, under award number DE-FOA-0002253.

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June 2, 2024
Yale Chemists Synthesize Elusive Anticancer Molecules

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Yale chemists have synthesized a unique class of anticancer molecules from bryozoans for the first time, marking a major advance in the field of synthetic chemistry. By employing a novel approach that combines strategic chemical processes and advanced structural determination techniques, the team has opened new possibilities for cancer treatment research.

Almost three decades ago, researchers identified a distinct group of anticancer compounds within bryozoans, a category of marine invertebrates native to tropical waters.

The chemical structures of these molecules, which consist of a dense, highly complex knot of oxidized rings and nitrogen atoms, have attracted the interest of organic chemists worldwide, who aimed to recreate these structures from scratch in the laboratory. However, despite considerable effort, it has remained an elusive task. Until now, that is.

A team of Yale chemists, writing in the journal Science, has succeeded in synthesizing eight of the compounds for the first time using an approach that combines inventive chemical strategy with the latest technology in small molecule structure determination.

“These molecules have been an outstanding challenge in the field of synthetic chemistry,” said Seth Herzon, the Milton Harris ’29 Ph.D. Professor of Chemistry in Yale’s Faculty of Arts and Sciences and corresponding author of the new study. “A number of research groups have tried to recreate these molecules in the lab, but their structures are so dense, so intricately connected, that it hasn’t been possible. I’ve been reading about efforts to synthesize these compounds since I was a graduate student in the early 2000s.”

Bryozoans: A Source of Novel Anticancer Agents

In nature, the molecules are found in some species of bryozoa — small, aquatic animals that feed by filtering prey from the water via tiny tentacles. Researchers worldwide consider bryozoans to be a potentially valuable source of new medications, and many molecules isolated from bryozoans have been studied as novel anticancer agents. However, the complexity of the molecules often limits their further development.

Herzon’s team looked at a particular species of bryozoa called Securiflustra securifrons.

“We worked on these molecules about a decade ago, and though we were not successful in recreating them at that time, we gleaned insight into their structure and chemical reactivity, which informed our thinking,” Herzon said.

Innovative Chemical Strategies

The new approach involved three key strategic elements. First, Herzon and his team avoided constructing a reactive heterocyclic ring, known as an indole, until the end of the process. A heterocyclic ring contains two or more elements — and this specific ring is known to be reactive and create problems, Herzon said.

Second, the researchers used methods known as oxidative photocyclizations to construct some of the key bonds in the molecules. One of these photocyclizations involved the reaction of a heterocycle with molecular oxygen, which was first studied by Yale’s Harry Wasserman in the 1960s.

Lastly, Herzon and his team employed microcrystal electron diffraction (MicroED) analysis to help visualize the structure of the molecules. Herzon said conventional methods for structure determination were inadequate in this context.

The result of the new approach is eight new synthetic molecules with therapeutic potential — and the promise of more new chemistry to come.

“These molecules hit right at my love of complex synthetic challenges,” said Herzon, who is also a member of the Yale Cancer Center and holds joint appointments in pharmacology and therapeutic radiology at Yale School of Medicine. “On a molecular weight basis, they are modest relative to other molecules we’ve studied in my lab. But from the vantage point of chemical reactivity, they present some of the greatest challenges we’ve ever taken on.”

Reference: “An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids” by Brandon W. Alexander, Noah M. Bartfield, Vaani Gupta, Brandon Q. Mercado, Mark Del Campo and Seth B. Herzon, 22 February 2024, Science.
DOI: 10.1126/science.adl6163

Co-first authors of the new study are Yale chemistry graduate students Brandon Alexander and Noah Bartfield. Co-authors are Vaani Gupta, a Yale chemistry graduate student; Brandon Mercado, a Yale X-ray crystallographer and lecturer in the Department of Chemistry; and Mark Del Campo of Rigaku Americas Corporation.

The National Science Foundation helped fund the research.

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March 6, 2024
New Study Synthesizes Key Compound in Lab

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Researchers have synthesized a key compound, pantetheine, under early Earth-like conditions, offering new insights into life’s origins. This breakthrough challenges previous notions about life’s beginnings in water, suggesting a simultaneous emergence of essential biological molecules, and paving the way for future explorations into the chemistry of life’s foundation.

A new study led by researchers at UCL has successfully synthesized a chemical compound in the laboratory under conditions that could have existed on early Earth, indicating its potential involvement in the emergence of life.

A new study led by researchers at UCL has synthesized a chemical compound critical to all forms of life under lab conditions that mimic those of early Earth, indicating its importance in the emergence of life.

The compound, pantetheine, is the active fragment of Coenzyme A. It is important for metabolism – the chemical processes that maintain life. Earlier studies failed to synthesize pantetheine effectively, leading to suggestions that it was absent at life’s origin.

In the new study, published in the journal Science, the research team created the compound in water at room temperature using molecules formed from hydrogen cyanide, which was likely abundant on early Earth.

Once formed, the researchers said, it is simple to envisage how pantetheine might have aided chemical reactions that led from simple forerunners of protein and RNA molecules to the first living organisms – a moment that is thought to have occurred 4 billion years ago.

The study challenges the view among some researchers in the field that water is too destructive for life to originate in it and that life more likely originated in pools that periodically dried out.

The Role of Aminonitriles

Driving the reactions that produced pantetheine were energy-rich molecules called aminonitriles, which are closely chemically related to amino acids, the building blocks of proteins and of life.

Members of the same team, led by Professor Matthew Powner (UCL Chemistry), have already used similar chemistry powered by aminonitriles to demonstrate how other key biological ingredients could be created at the origin of life, including peptides (protein-creating chains of amino acids) and nucleotides (the building blocks of RNA and DNA).

Professor Powner, senior author of the paper, said: “This new study is further evidence that the basic structures of biology, the primary molecules that biology is built from, are predisposed to form through nitrile chemistry.

“The ease with which different classes of biological molecules can be made using nitriles has convinced me that, rather than life being preceded by one molecule such as RNA, and there being an ‘RNA world’ before life began, the basic molecules of biology emerged alongside each other – a network of RNAs, proteins, enzymes and cofactors leading to the first living organisms.

“Our future work will look at how these molecules came together, how pantetheine chemistry talks to RNA, peptide, and lipid chemistry for instance, to deliver chemistry that the individual classes of molecule could not deliver in isolation.”

Future Directions and Historical Context

A notable earlier attempt to synthesize pantetheine was made in 1995 by the late American chemist Stanley Miller, who had started the field of origin of life experiments three decades earlier, creating amino acids from four simple chemicals in glass tubes.

However, in the later 1995 experiment, the yields of pantetheine were very low and required extremely high concentrations of chemicals that had been dried out and sealed in an airtight tube before they were heated to 100 degrees Centigrade.

Dr. Jasper Fairchild (UCL Chemistry), a lead author of the study, who conducted the work as part of his PhD, said: “The major difference between Miller’s study and ours is whereas Miller tried to use acid chemistry, we used nitriles. It’s the nitriles that bring the energy and the selectivity. Our reactions just run in water and produce high yields of pantetheine with relatively low concentrations of chemicals needed.”

Professor Powner added: “It had been assumed you should make these molecules from acids, because using acids appears to be biological, and that is what we are taught at school and at university. We are taught peptides are made from amino acids.

“Our work suggests this conventional view has ignored an essential ingredient, the energy required to forge new bonds. The reactions look a little different with nitriles but the end products – the basic units of biology – are indistinguishable whether formed through acid or nitrile chemistry.”

While the paper focuses solely on the chemistry, the research team said that the reactions they demonstrated could plausibly have taken place in pools or lakes of water on the early Earth (but not likely in the oceans as the concentrations of the chemicals would likely be too diluted).

Reference: “Prebiotically plausible chemoselective pantetheine synthesis in water” by Jasper Fairchild, Saidul Islam, Jyoti Singh, Dejan-Krešimir Bučar and Matthew W. Powner, 22 February 2024, Science.
DOI: 10.1126/science.adk4432

The new study was supported by the Engineering and Physical Sciences Research Council, the Simons Foundation, and the Volkswagen Foundation.

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February 25, 2024