̽��ֱ�� of Cambridge - Molecule

New form of ice is like a snapshot of liquid water

cr696 — Thu, 02 Feb 2023 19:00:00 +0000

̽��ֱ��new form of ice is amorphous. Unlike ordinary crystalline ice where the molecules arrange themselves in a regular pattern, in amorphous ice the molecules are in a disorganised form that resembles a liquid.

In their paper, published in Science, the team created a new form of amorphous ice in experiment and achieved an atomic-scale model of it in computer simulation. ̽��ֱ��experiments used a technique called ball-milling, which grinds crystalline ice into small particles using metal balls in a steel jar. Ball-milling is regularly used to make amorphous materials, but it had never been applied to ice.

̽��ֱ��team found that ball-milling created an amorphous form of ice, which unlike all other known ices, had a density similar to that of liquid water and whose state resembled water in solid form. They named the new ice medium-density amorphous ice (MDA).

To understand the process at the molecular scale the team employed computational simulation. By mimicking the ball-milling procedure via repeated random shearing of crystalline ice, the team successfully created a computational model of MDA.

“Our discovery of MDA raises many questions on the very nature of liquid water and so understanding MDA’s precise atomic structure is very important,” said co-author Dr Michael Davies, who carried out the computational modelling. “We found remarkable similarities between MDA and liquid water.”

A happy medium

Amorphous ices have been suggested to be models for liquid water. Until now, there have been two main types of amorphous ice: high-density and low-density amorphous ice.

As the names suggest, there is a large density gap between them. This density gap, combined with the fact that the density of liquid water lies in the middle, has been a cornerstone of our understanding of liquid water. It has led in part to the suggestion that water consists of two liquids: one high- and one low-density liquid.

Senior author Professor Christoph Salzmann said: “ ̽��ֱ��accepted wisdom has been that no ice exists within that density gap. Our study shows that the density of MDA is precisely within this density gap and this finding may have far-reaching consequences for our understanding of liquid water and its many anomalies.”

A high-energy geophysical material

̽��ֱ��discovery of MDA gives rise to the question: where might it exist in nature? Shear forces were discovered to be key to creating MDA in this study. ̽��ֱ��team suggests ordinary ice could undergo similar shear forces in the ice moons due to the tidal forces exerted by gas giants such as Jupiter.

Moreover, MDA displays one remarkable property that is not found in other forms of ice. Using calorimetry, they found that when MDA recrystallises to ordinary ice it releases an extraordinary amount of heat. ̽��ֱ��heat released from the recrystallization of MDA could play a role in activating tectonic motions. More broadly, this discovery shows water can be a high-energy geophysical material.

Professor Angelos Michaelides, lead author from Cambridge's Yusuf Hamied Department of Chemistry, said: “Amorphous ice in general is said to be the most abundant form of water in the universe. ̽��ֱ��race is now on to understand how much of it is MDA and how geophysically active MDA is.”

Reference:
Alexander Rosu-Finsen et al. 'Medium-density amorphous ice.' Science (2023). DOI: 10.1126/science.abq2105

A collaboration between scientists at Cambridge and UCL has led to the discovery of a new form of ice that more closely resembles liquid water than any other and may hold the key to understanding this most famous of liquids.

Our discovery of MDA raises many questions on the very nature of liquid water and so understanding MDA’s precise atomic structure is very important

Michael Davies

Christoph Salzmann

Part of the set-up for creating medium-density amorphous ice: ordinary ice and steel balls in a jar (not amorphous ice)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Method to predict drug stability could lead to more effective medicines

sc604 — Mon, 05 Mar 2018 14:10:10 +0000

̽��ֱ��researchers, from the Universities of Cambridge and Copenhagen, have developed a new method to solve an old problem: how to predict when and how a solid will crystallise. Using optical and mechanical measuring techniques, they found that localised movement of molecules within a solid is ultimately responsible for crystallisation.

This solution to the problem was first proposed in 1969, but it has only now become possible to prove the hypothesis. ̽��ֱ��results are reported in two papers in Physical Chemistry Chemical Physics and ̽��ֱ��Journal of Physical Chemistry B.

Solids behave differently depending on whether their molecular structure is ordered (crystal) or disordered (glass). Chemically, the crystal and glass forms of a solid are exactly the same, but they have different properties.

One of the desirable properties of glasses is that they are more soluble in water, which is especially useful for medical applications. To be effective, medicines need to be water-soluble, so that they can be dissolved within the body and reach their target via the bloodstream.

“Most of the medicines in use today are in the crystal form, which means that they need extra energy to dissolve in the body before they enter the bloodstream,” said study co-author Professor Axel Zeitler from Cambridge’s Department of Chemical Engineering & Biotechnology. “Molecules in the glass form are more readily absorbed by the body because they can dissolve more easily, and many glasses that can cure disease have been discovered in the past 20 years, but they’re not being made into medicines because they’re not stable enough.”

After a certain time, all glasses will undergo spontaneous crystallisation, at which point the molecules will not only lose their disordered structure, but they will also lose the properties that made them effective in the first place. A long-standing problem for scientists has been how to predict when crystallisation will occur, which, if solved, would enable the widespread practical application of glasses.

“This is a very old problem,” said Zeitler. “And for pharmaceutical companies, it’s often too big of a risk. If they develop a drug based on the glass form of a molecule and it crystallises, they will not only have lost a potentially effective medicine, but they would have to do a massive recall.”

In order to determine when and how solids will crystallise, most researchers had focused on the glass transition temperature, which is the temperature above which molecules can move in the solid more freely and can be measured easily. Using a technique called dynamic mechanical analysis as well as terahertz spectroscopy, Zeitler and his colleagues showed that instead of the glass transition temperature_, the molecular motions occurring until a lower temperature threshold, are responsible for crystallisation.

These motions are constrained by localised forces in the molecular environment and, in contrast to the relatively large motions that happen above the glass transition temperature_, the molecular motions above the lower temperature threshold are much subtler. While the localised movement is tricky to measure, it is a key part of the crystallisation process.

Given the advance in measurement techniques developed by the Cambridge and Copenhagen teams, drug molecules that were previously discarded at the pre-clinical stage can now be tested to determine whether they can be brought to the market in a stable glass form that overcomes the solubility limitations of the crystal form.

“If we use our technique to screen molecules that were previously discarded, and we find that the temperature associated with the onset of the localised motion is sufficiently high, we would have high confidence that the material will not crystallise following manufacture,” said Zeitler. “We could use the calibration curve that we describe in the second paper to predict the length of time it will take the material to crystallise.”

̽��ֱ��research has been patented and is being commercialised by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm. ̽��ֱ��research was funded by the Engineering and Physical Sciences Research Council (EPSRC).

References:
Michael T. Ruggiero et al. ‘ ̽��ֱ��significance of the amorphous potential energy landscape for dictating glassy dynamics and driving solid-state crystallisation’ Physical Chemistry Chemical Physics, 19, 30039-30047 (2017). DOI: 10.1039/c7cp06664c

Eric Ofosu Kissi et al. ‘ ̽��ֱ��glass transition temperature of the β-relaxation as the single predictive parameter for recrystallization of neat amorphous drugs.’ ̽��ֱ��Journal of Physical Chemistry B (2018). DOI: 10.1021/acs.jpcb.7b10105

Researchers from the UK and Denmark have developed a new method to predict the physical stability of drug candidates, which could help with the development of new and more effective medicines for patients. ̽��ֱ��technology has been licensed to Cambridge spin-out company TeraView, who are developing it for use in the pharmaceutical industry in order to make medicines that are more easily released in the body.

This is a very old problem, and for pharmaceutical companies, it’s often too big of a risk.

Axel Zeitler

Gatis Gribusts

Medication

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Licence type:

Attribution-Noncommerical

Silk “micrococoons” could be used in biotechnology and medicine

tdk25 — Wed, 19 Jul 2017 07:56:41 +0000

Microscopic versions of the cocoons spun by silkworms have been manufactured by a team of researchers. ̽��ֱ��tiny capsules, which are invisible to the naked eye, can protect sensitive molecular materials, and could prove a significant technology in areas including food science, biotechnology and medicine.

̽��ֱ��capsules were made at the ̽��ֱ�� of Cambridge using a specially-developed microengineering process that combines the power of microfluidic manufacturing with the value of natural silk. ̽��ֱ��process mimics on the microscale the way in which Bombyx mori silkworms spin the cocoons from which natural silk is harvested. ̽��ֱ��resulting micron-scale capsules comprise a solid and tough shell of silk nano-fibrils that surround and protect a centre of liquid cargo, and are more than thousand times smaller than those created by silkworms.

Writing in the journal Nature Communications, the team suggest that these “micrococoons” are a potential solution to a common technological problem: How to protect sensitive molecules that have potential health or nutritional benefits, but can easily degrade and lose these favourable qualities during storage or processing.

̽��ֱ��study argues that sealing such molecules in a protective layer of silk could be the answer, and that silk micrococoons that are far too small to see (or taste) could be used to house tiny particles of beneficial molecular “cargo” in various products, such as cosmetics and food.

̽��ֱ��same technology could also be used in pharmaceuticals to treat a wide range of severe and debilitating illnesses. In the study, the researchers successfully showed that silk micrococoons can increase the stability and lifetime of an antibody that acts on a protein implicated in neurodegenerative diseases.

̽��ֱ��work was carried out by an international team of academics from the Universities of Cambridge, Oxford and Sheffield in the UK; the Swiss Federal Institute of Technology in Zurich, Switzerland; and the Weizmann Institute of Science in Israel. ̽��ֱ��study was led by Professor Tuomas Knowles, a Fellow of St John’s College at the ̽��ֱ�� of Cambridge and co-director of the Centre for Protein Misfolding Diseases.

“It is a common problem in a range of areas of great practical importance to have active molecules that possess beneficial properties but are challenging to stabilise for storage” Knowles said. “A conceptually simple, but powerful, solution is to put these inside tiny capsules. Such capsules are typically made from synthetic polymers, which can have a number of drawbacks, and we have recently been exploring the use of fully natural materials for this purpose. We are particularly excited by the potential to replace plastics with sustainable biological materials for this purpose.”

Dr. Ulyana Shimanovich, who performed a major part of the experimental work as a St John’s College Post-Doctoral research associate, and now works at the Weizmann Institute of Science, said: “Silk is a fantastic example of a natural structural material. But we had to overcome the challenge of controlling the silk to the extent that we could mould it to our designs which are more than a factor of a thousand smaller than the natural silk cocoons.”

Dr. Chris Holland, co-worker and head of the Natural Materials Group in Sheffield added: “Silk is amazing because whilst it is stored as a liquid, spinning transforms it into a solid. This is achieved by stretching the silk proteins as they flow down a microscopic tube inside the silkworm.”

To imitate this, the researchers created a tiny, artificial spinning duct, which copies the natural spinning process to cause the unspun silk to form into a solid. ̽��ֱ��researchers then worked out how to control the geometry of this self-assembly in order to create microscopic shells.

Making conventional synthetic capsules can be challenging to achieve in an environmentally friendly manner and from biodegradable and biocompatible materials. Silk is not only easier to produce; it is also biodegradable and requires less energy to manufacture.

“Natural silk is already being used in products like surgical materials, so we know that it is safe for human use,” Professor Fritz Vollrath head of the Oxford Silk Group said. “Importantly, the approach does not change the material, just its shape.”

Silk micrococoons could also expand the range and shelf-life of proteins and molecules available for pharmaceutical use. Because the technology can preserve antibodies, which would otherwise degrade, in cocoons with walls that can be designed to dissolve over time, it could enable the development of new treatments against cancer, or neurodegenerative conditions such as Alzheimer’s and Parkinson’s Diseases.

To explore the viability of silk microcapsules in this regard, the researchers successfully tested the micrococoons with an antibody that has been developed to act on alpha-synuclein, the protein that is thought to malfunction at the start of the molecular process leading to Parkinson’s Disease. This study was carried out with the support of the Cambridge Centre for Misfolding Diseases, whose research programme is focused on the search for ways of preventing and treating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Professor Chris Dobson, Director of the Centre and Master of St John's, who is also a co-author of this paper, said: " ̽��ֱ��results of this study are extremely exciting as they suggest that many potentially therapeutic molecules that could not normally be taken forward into the clinic because of their lack of stability, could become life-changing drugs using these encapsulation techniques."

“Some of the most efficacious and largest selling therapeutics are antibodies,” Michele Vendruscolo, co-director of the Cambridge Centre of Misfolding diseases, said. “However, antibodies tend to be prone to aggregation at the high concentrations needed for delivery, which means that they are often written off for use in treatments, or have to be engineered to promote stability.”

“By containing such antibodies in micrococoons, as we did here, we could significantly extend not just their longevity, but also the range of antibodies at our disposal,” Knowles said. “We are very excited by the possibilities of using the power of microfluidics to generate entirely new types of artificial materials from fully natural proteins.“

̽��ֱ��study, Silk microcooons for protein stabilisation and molecular encapsulation, is published in Nature Communications.

Researchers have manufactured microscopic versions of the cocoons spun by silkworms, which could be used to store sensitive proteins and other molecules for a wide range of uses.

By containing antibodies in micrococoons, as we did here, we could significantly extend not just their longevity, but also the range of antibodies at our disposal.

Tuomas Knowles

Credit: 2017 Natural Materials Group

̽��ֱ��silkworm spins a silk cocoon around itself for protection during metamorphosis. Researchers have found that silk can also protect other precious molecular cargo.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Molecular inhibitor breaks cycle that leads to Alzheimer’s

tdk25 — Mon, 16 Feb 2015 16:00:28 +0000

A molecule that can block the progress of Alzheimer’s disease at a crucial stage in its development has been identified by researchers in a new study, raising the prospect that more such molecules may now be found.

̽��ֱ��report shows that a molecular chaperone, a type of molecule that occurs naturally in humans, can play the role of an “inhibitor” part-way through the molecular process that is thought to cause Alzheimer’s, breaking the cycle of events that scientists believe leads to the disease.

Specifically, the molecule, called Brichos, sticks to threads made up of malfunctioning proteins, called amyloid fibrils, which are the hallmark of the disease. By doing so, it stops these threads from coming into contact with other proteins, thereby helping to avoid the formation of highly toxic clusters that enable the condition to proliferate in the brain.

This step – where fibrils made up of malfunctioning proteins assist in the formation of toxic clusters – is considered to be one of the most critical stages in the development of Alzheimer’s in sufferers. By finding a molecule that prevents it from occurring, scientists have moved closer to identifying a substance that could eventually be used to treat the disease. ̽��ֱ��discovery was made possible by an overall strategy that could now be applied to find other molecules with similar capabilities, extending the range of options for future drug development.

̽��ֱ��research was carried out by an international team comprising academics from the Department of Chemistry at the ̽��ֱ�� of Cambridge, the Karolinska Institute in Stockholm, Lund ̽��ֱ��, the Swedish ̽��ֱ�� of Agricultural Sciences, and Tallinn ̽��ֱ��. Their findings are reported in the journal Nature Structural & Molecular Biology.

Dr Samuel Cohen, a Research Fellow at St John’s College, Cambridge, and a lead author of the report, said: “A great deal of work in this field has gone into understanding which microscopic processes are important in the development of Alzheimer’s disease; now we are now starting to reap the rewards of this hard work. Our study shows, for the first time, one of these critical processes being specifically inhibited, and reveals that by doing so we can prevent the toxic effects of protein aggregation that are associated with this terrible condition.”

Alzheimer’s disease is one of a number of conditions caused by naturally occurring protein molecules folding into the wrong shape and then sticking together – or nucleating – with other proteins to create thin filamentous structures called amyloid fibrils. Proteins perform important functions in the body by folding into a particular shape, but sometimes they can misfold, potentially kick-starting this deadly process.

Recent research, much of it by the academics behind the latest study, has however suggested a second critical step in the disease’s development. After amyloid fibrils first form from misfolded proteins, they help other proteins which come into contact with them to misfold and form small clusters, called oligomers. These oligomers are highly toxic to nerve cells and are now thought to be responsible for the devastating effects of Alzheimer's disease.

This second stage, known as secondary nucleation, sets off a chain reaction which creates many more toxic oligomers, and ultimately amyloid fibrils, generating the toxic effects that eventually manifest themselves as Alzheimer’s. Without the secondary nucleation process, single molecules would have to misfold and form toxic clusters unaided, which is a much slower and far less devastating process.

By studying the molecular processes by which each of these steps takes effect, the research team assembled a wealth of data that enabled them to model not only what happens during the progression of Alzheimer’s disease, but also what might happen if one stage in the process was somehow switched off.

“We had reached a stage where we knew what the data should look like if we inhibited any given step in the process, including secondary nucleation,” Cohen said. “Working closely with our collaborators in Sweden - who had developed groundbreaking experimental methods to monitor the process - we were able to identify a molecule that produced exactly the results that we were hoping to see in experiments.”

̽��ֱ��results indicated that the molecule, Brichos, effectively inhibits secondary nucleation. Typically, Brichos functions as a “molecular chaperone” in humans; a term given to "housekeeping" molecules that help proteins to avoid misfolding and aggregation. Lab tests, however, revealed that when this molecular chaperone encounters an amyloid fibril, it binds itself to catalytic sites on its surface. This essentially forms a coating that prevents the fibrils from assisting other proteins in misfolding and nucleating into toxic oligomers.

̽��ֱ��research team then carried out further tests in which living mouse brain tissue was exposed to amyloid-beta, the specific protein that forms the amyloid fibrils in Alzheimer’s disease. Allowing the amyloid-beta to misfold and form amyloids increased toxicity in the tissue significantly. When this happened in the presence of the molecular chaperone, however, amyloid fibrils still formed but the toxicity did not develop in the brain tissue, confirming that the molecule had suppressed the chain reaction from secondary nucleation that feeds the catastrophic production of oligomers leading to Alzheimer’s disease.

By modelling what might happen if secondary nucleation is switched off and then finding a molecule that performs that function, the research team suggest that they have discovered a strategy that may lead to the identification of other molecules that could have a similar effect.

“It may not actually be too difficult to find other molecules that do this, it’s just that it hasn't been clear what to look for until recently,” Cohen said. “It's striking that nature – through molecular chaperones – has evolved a similar approach to our own by focusing on very specifically inhibiting the key steps leading to Alzheimer's. A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy.”

̽��ֱ��other members of the Cambridge team were Dr Tuomas Knowles, Dr Paolo Arosio, Professor Michele Vendruscolo and Professor Chris Dobson. All are members of the Centre for Misfolding Diseases, which is based in the ̽��ֱ��'s Department of Chemistry.

A molecular chaperone has been found to inhibit a key stage in the development of Alzheimer’s disease and break the toxic chain reaction that leads to the death of brain cells, a new study shows. ̽��ֱ��research provides an effective basis for searching for candidate molecules that could be used to treat the condition.

It may not actually be too difficult to find other molecules that do this, it’s just that it hasn't been clear what to look for until recently. A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy.

Sam Cohen

S. Cohen

Transmission electron microscopy image showing a molecular chaperone (the black dots) binding to thread-like amyloid-beta (Aβ42)

̽��ֱ��text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

Yes

World’s first artificial enzymes created using synthetic biology

tdk25 — Mon, 01 Dec 2014 16:00:00 +0000

A team of researchers have created the world’s first enzymes made from artificial genetic material.

̽��ֱ��synthetic enzymes, which are made from molecules that do not occur anywhere in nature, are capable of triggering chemical reactions in the lab.

̽��ֱ��research is published in the journal Nature and promises to offer new insights into the origins of life, as well as providing a potential starting point for an entirely new generation of drugs and diagnostics. In addition, the authors speculate that the study increases the range of planets that could potentially host life.

All life on Earth depends on the chemical transformations that enable cellular function and the performance of basic tasks, from digesting food to making DNA. These are powered by naturally-occurring enzymes which operate as catalysts, kick-starting the process and enabling such reactions to happen at the necessary rate.

For the first time, however, the research shows that these natural biomolecules may not be the only option, and that artificial enzymes could also be used to power the reactions that enable life to occur.

̽��ֱ��findings build on previous work in which the scientists, from the MRC Laboratory of Molecular Biology in Cambridge and the ̽��ֱ�� of Cambridge, created synthetic molecules called “XNAs”. These are entirely artificial genetic systems that can store and pass on genetic information in a manner similar to DNA.

Using these XNAs as building blocks, the new research involved the creation of so-called “XNAzymes”. Like naturally occurring enzymes, these are capable of powering simple biochemical reactions.

Dr Alex Taylor, a Post-doctoral Researcher at St John’s College, ̽��ֱ�� of Cambridge, who is based at the MRC Laboratory and was the study’s lead author, said: “ ̽��ֱ��chemical building blocks that we used in this study are not naturally-occurring on Earth, and must be synthesised in the lab. This research shows us that our assumptions about what is required for biological processes – the ‘secret of life’ – may need some further revision. ̽��ֱ��results imply that our chemistry, of DNA, RNA and proteins, may not be special and that there may be a vast range of alternative chemistries that could make life possible.”

Every one of our cells contains thousands of different enzymes, many of which are proteins. In addition, however, nucleic acids – DNA and its close chemical cousin, RNA – can also form enzymes. ̽��ֱ��ribosome, the molecular machine which manufactures proteins within all cells, is an RNA enzyme. Life itself is widely thought to have begun with the emergence of a self-copying RNA enzyme.

Dr Philipp Holliger, from the MRC Laboratory of Molecular Biology, said: “Until recently it was thought that DNA and RNA were the only molecules that could store genetic information and, together with proteins, the only biomolecules able to form enzymes.”

“Our work suggests that, in principle, there are a number of possible alternatives to nature’s molecules that will support the catalytic processes required for life. Life’s ‘choice’ of RNA and DNA may just be an accident of prehistoric chemistry.”

“ ̽��ֱ��creation of synthetic DNA, and now enzymes, from building blocks that don’t exist in nature also raises the possibility that if there is life on other planets it may have sprung up from an entirely different set of molecules, and widens the possible number of planets that might be able to host life.”

̽��ֱ��group’s previous study, carried out in 2012, showed that six alternative molecules, called XNAs, could store genetic information and evolve through natural selection. Expanding on that principle, the new research identified, for the first time, four different types of synthetic catalyst formed from these entirely unnatural building blocks.

These XNAzymes are capable of catalysing simple reactions, like cutting and joining strands of RNA in a test tube. One of the XNAzymes can even join strands together, which represents one of the first steps towards creating a living system.

Because their XNAzymes are much more stable than naturally occurring enzymes, the scientists believe that they could be particularly useful in developing new therapies for a range of diseases, including cancers and viral infections, which exploit the body’s natural processes.

Dr Holliger added: “Our XNAs are chemically extremely robust and, because they do not occur in nature, they are not recognised by the body’s natural degrading enzymes. This might make them an attractive candidate for long-lasting treatments that can disrupt disease-related RNAs.”

Professor Patrick Maxwell, Chair of the MRC’s Molecular and Cellular Medicine Board and Regius Professor of Physic at the ̽��ֱ�� of Cambridge, said: “Synthetic biology is delivering some truly amazing advances that promise to change the way we understand and treat disease. ̽��ֱ��UK excels in this field, and this latest advance offers the tantalising prospect of using designer biological parts as a starting point for an entirely new class of therapies and diagnostic tools that are more effective and have a longer shelf-life.”

Funders of the research included the MRC, European Science Foundation and the Biotechnology and Biological Sciences Research Council.

Enzymes made from artificial molecules which do not occur anywhere in nature have been shown to trigger chemical reactions in the lab, challenging existing views about the conditions that are needed to enable life to happen.

Our assumptions about what is required for biological processes – the ‘secret of life’ – may need some further revision

Alex Taylor

A. Taylor

̽��ֱ��study built on previous work which created synthetic molecules known as “XNA”, then used these as the basis of creating so-called “XNAzymes”.

Yes