Supramolecular chemistry: Self-constructed folded macrocycles with low symmetry

Molecules that are made up of multiple repeating subunits, known as monomers, which may vary or not in their chemical structure, are classified as macromolecules or polymers. Examples exist in nature, including proteins and nucleic acids, which are at the heart of all biological systems. Proteins not only form the basis of structural elements in cells, they also serve as enzymes — which catalyze essentially all of the myriad of chemical transformations that take place in living systems. In contrast, nucleic acids such as DNA and RNA serve as informational macromolecules. DNA stores the cell’s genetic information, which is selectively copied into RNA molecules that provide the blueprints for the synthesis of proteins. In addition, long chains comprised of sugar units provide energy reserves in the form of glycogen, which is stored in the liver and the muscles. These diverse classes of polymeric molecules all have one feature in common: They spontaneously fold into characteristic spatial conformations, for example the famous DNA double helix, which in most cases are essential for their biochemical functions.

Professor Ivan Huc (Department of Pharmacy, LMU) studies aspects of the self-organization processes that enable macromolecules to adopt defined folded shapes. The molecular structures found in nature provide him with models, whose properties he tries to reproduce in the laboratory with non-natural molecules that are neither proteins, nucleic acids or sugar-like. More specifically, he uses the tools of synthetic chemistry to elucidate the underlying principles of self-organization — by constructing molecules that are expressly designed to fold into predetermined shapes. Beginning with monomers that his group has developed, he sets out to produce what he calls ‘foldamers’, by assembling the monomers one by one to generate a folded macromolecule.

Structures with low degrees of symmetry

“The normal way to get the complex structure of proteins is to use different types of monomers, called amino acids,” as Huc reports. “And the normal method to connect different amino acids in the the correct order is to link them one by one.” The sequence of amino acids contains the folding information that allows different protein sequences to fold in different ways.

“But we discovered something unexpected and spectacular,” comments Huc. He and his colleagues in Munich, Groningen, Bordeaux and Berlin used organic, sulfur-containing monomers to spontaneously get cyclic macromolecules with a complex shape, as illustrated by their low degree of symmetry, without requiring a specific sequence. The macromolecules self-synthesize — no further conditions are necessary. “We only put one monomer type in a flask and wait,” Huc says. “This is typical for a polymerization reaction, but polymers from a single monomer usually don´t adopt complex shapes and don’t stop growing at a precise chain length.”

To further control the reaction, the scientists also used either a small guest molecule or a metal ion. The regulator binds within the growing macromolecule and causes monomers to arrange themselves around it. By choosing a regulator with the appropriate characteristics, the authors of the new study were able to produce structures with a predetermined number of subunits. The cyclic macromolecules exhibited low levels of symmetry. Some consisted of either 13, 17 or 23 subunits. Since 13, 17 and 23 are prime numbers, the corresponding folded shapes exhibit low degrees of symmetry.

A model for biological and industrial processes

Interest in the elucidation of such mechanisms is not restricted to the realm of basic research. Huc and his colleagues hope that their approach will lead to the fabrication of designer plastics. Conventional polymers usually consist of mixtures of molecules that vary in length (i.e. the number of monomers they contain). This heterogeneity has an impact on their physical properties. Hence, the ability to synthesize polymer chains of an exact length and/or geometry is expected to lead to materials with novel and interesting behaviors.

Furthermore, foldamers like those that have now been synthesized show close structural resemblances to biopolymers. They therefore offer an ideal model system in which to study the properties of proteins. Every protein is made up of a defined linear (i.e. unbranched) sequence of amino acids, which constitutes its ‘primary structure’. But most amino-acid chains fold into local substructures such as helically coiled stretches, or parallel strands that can form sheets. These units represent the protein’s secondary structure. The term ‘tertiary structure’ is applied to the fully folded single chain. This in turn can interact with other chains to form a functional unit or quaternary structure.

Huc’s ultimate goal is to mimic complex biological mechanisms using structurally defined, synthetic precursors. He wants to understand how, for example, enzymes fold into the correct, biologically active conformation following their synthesis in cells. Molecules whose properties can be precisely controlled in the laboratory provide ideal models with which to work out the answers and perhaps to go beyond enzymes themselves.

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Materials provided by Ludwig-Maximilians-Universität München. Note: Content may be edited for style and length.

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Astronomers detect regular rhythm of radio waves, with origins unknown

A team of astronomers, including researchers at MIT, has picked up on a curious, repeating rhythm of fast radio bursts emanating from an unknown source outside our galaxy, 500 million light years away.

Fast radio bursts, or FRBs, are short, intense flashes of radio waves that are thought to be the product of small, distant, extremely dense objects, though exactly what those objects might be is a longstanding mystery in astrophysics. FRBs typically last a few milliseconds, during which time they can outshine entire galaxies.

Since the first FRB was observed in 2007, astronomers have catalogued over 100 fast radio bursts from distant sources scattered across the universe, outside our own galaxy. For the most part, these detections were one-offs, flashing briefly before disappearing entirely. In a handful of instances, astronomers observed fast radio bursts multiple times from the same source, though with no discernible pattern.

This new FRB source, which the team has catalogued as FRB 180916.J0158+65, is the first to produce a periodic, or cyclical pattern of fast radio bursts. The pattern begins with a noisy, four-day window, during which the source emits random bursts of radio waves, followed by a 12-day period of radio silence.

The astronomers observed that this 16-day pattern of fast radio bursts reoccurred consistently over 500 days of observations. “This FRB we’re reporting now is like clockwork,” says Kiyoshi Masui, assistant professor of physics in MIT’s Kavli Institute for Astrophysics and Space Research. “It’s the most definitive pattern we’ve seen from one of these sources. And it’s a big clue that we can use to start hunting down the physics of what’s causing these bright flashes, which nobody really understands.”

Masui is a member of the CHIME/FRB collaboration, a group of more than 50 scientists led by the University of British Columbia, McGill University, University of Toronto, and the National Research Council of Canada, that operates and analyzes the data from the Canadian Hydrogen Intensity Mapping Experiment, or CHIME, a radio telescope in British Columbia that was the first to pick up signals of the new periodic FRB source.

The CHIME/FRB Collaboration has published the details of the new observation today in the journal Nature.

A radio view

In 2017, CHIME was erected at the Dominion Radio Astrophysical Observatory in British Columbia, where it quickly began detecting fast radio bursts from galaxies across the universe, billions of light years from Earth.

CHIME consists of four large antennas, each about the size and shape of a snowboarding half-pipe, and is designed with no moving parts. Rather than swiveling to focus on different parts of the sky, CHIME stares fixedly at the entire sky, using digital signal processing to pinpoint the region of space where incoming radio waves are originating.

From September 2018 to February 2020, CHIME picked out 38 fast radio bursts from a single source, FRB 180916.J0158+65, which the astronomers traced to a star-churning region on the outskirts of a massive spiral galaxy, 500 million light years from Earth. The source is the most active FRB source that CHIME has yet detected, and until recently it was the closest FRB source to Earth.

As the researchers plotted each of the 38 bursts over time, a pattern began to emerge: One or two bursts would occur over four days, followed by a 12-day period without any bursts, after which the pattern would repeat. This 16-day cycle occurred again and again over the 500 days that they observed the source.

“These periodic bursts are something that we’ve never seen before, and it’s a new phenomenon in astrophysics,” Masui says.

Circling scenarios

Exactly what phenomenon is behind this new extragalactic rhythm is a big unknown, although the team explores some ideas in their new paper. One possibility is that the periodic bursts may be coming from a single compact object, such as a neutron star, that is both spinning and wobbling — an astrophysical phenomenon known as precession. Assuming that the radio waves are emanating from a fixed location on the object, if the object is spinning along an axis and that axis is only pointed toward the direction of Earth every four out of 16 days, then we would observe the radio waves as periodic bursts.

Another possibility involves a binary system, such as a neutron star orbiting another neutron star or black hole. If the first neutron star emits radio waves, and is on an eccentric orbit that briefly brings it close to the second object, the tides between the two objects could be strong enough to cause the first neutron star to deform and burst briefly before it swings away. This pattern would repeat when the neutron star swings back along its orbit.

The researchers considered a third scenario, involving a radio-emitting source that circles a central star. If the star emits a wind, or cloud of gas, then every time the source passes through the cloud, the gas from the cloud could periodically magnify the source’s radio emissions.

“Maybe the source is always giving off these bursts, but we only see them when it’s going through these clouds, because the clouds act as a lens,” Masui says.

Perhaps the most exciting possibility is the idea that this new FRB, and even those that are not periodic or even repeating, may originate from magnetars — a type of neutron star that is thought to have an extremely powerful magnetic field. The particulars of magnetars are still a bit of a mystery, but astronomers have observed that they do occasionally release massive amounts of radiation across the electromagnetic spectrum, including energy in the radio band.

“People have been working on how to make these magnetars emit fast radio bursts, and this periodicity we’ve observed has since been worked into these models to figure out how this all fits together,” Masui says.

Very recently, the same group made a new observation that supports the idea that magnetars may in fact be a viable source for fast radio bursts. In late April, CHIME picked up a signal that looked like a fast radio burst, coming from a flaring magnetar, some 30,000 light years from Earth. If the signal is confirmed, this would be the first FRB detected within our own galaxy, as well as the most compelling evidence of magnetars as a source of these mysterious cosmic sparks.

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