Tag Archives: protein-folding

The character of water: both types

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This is to use an old term, ‘mindblowing’. Apparently, there are two types of the liquid we call water according to a Nov. 10, 2016 news item on phys.org,

There are two types of liquid water, according to research carried out by an international scientific collaboration. This new peculiarity adds to the growing list of strange phenomena in what we imagine is a simple substance. The discovery could have implications for making and using nanoparticles as well as in understanding how proteins fold into their working shape in the body or misfold to cause diseases such as Alzheimer’s or CJD [Creutzfeldt-Jakob Disease].

A Nov. 10, 2016 Inderscience Publishers news release, which originated the news item, expands on the theme,

Writing in the International Journal of Nanotechnology, Oxford University’s Laura Maestro and her colleagues in Italy, Mexico, Spain and the USA, explain how the physical and chemical properties of water have been studied for more than a century and revealed some odd behavior not seen in other substances. For instance, when water freezes it expands. By contrast, almost every other known substance contracts when it is cooled. Water also exists as solid, liquid and gas within a very small temperature range (100 degrees Celsius) whereas the melting and boiling points of most other compounds span a much greater range.

Many of water’s bizarre properties are due to the molecule’s ability to form short-lived connections with each other known as hydrogen bonds. There is a residual positive charge on the hydrogen atoms in the V-shaped water molecule either or both of which can form such bonds with the negative electrons on the oxygen atom at the point of the V. This makes fleeting networks in water possible that are frozen in place when the liquid solidifies. They bonds are so short-lived that they do not endow the liquid with any structure or memory, of course.

The team has looked closely at several physical properties of water like its dielectric constant (how well an electric field can permeate a substance) or the proton-spin lattice relaxation (the process by which the magnetic moments of the hydrogen atoms in water can lose energy having been excited to a higher level). They have found that these phenomena seem to flip between two particular characters at around 50 degrees Celsius, give or take 10 degrees, i.e. from 40 to 60 degrees Celsius. The effect is that thermal expansion, speed of sound and other phenomena switch between two different states at this crossover temperature.

These two states could have important implications for studying and using nanoparticles where the character of water at the molecule level becomes important for the thermal and optical properties of such particles. Gold and silver nanoparticles are used in nanomedicine for diagnostics and as antibacterial agents, for instance. Moreover, the preliminary findings suggest that the structure of liquid water can strongly influence the stability of proteins and how they are denatured at the crossover temperature, which may well have implications for understanding protein processing in the food industry but also in understanding how disease arises when proteins misfold.

Here’s a link to and a citation for the paper,

On the existence of two states in liquid water: impact on biological and nanoscopic systems
by L.M. Maestro, M.I. Marqués, E. Camarillo, D. Jaque, J. García Solé, J.A. Gonzalo, F. Jaque, Juan C. Del Valle, F. Mallamace, H.E. Stanley.
International Journal of Nanotechnology (IJNT), Vol. 13, No. 8/9, 2016 DOI: 10.1504/IJNT.2016.079670

This paper is behind a paywall.

I hear the proteins singing

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Points to anyone who recognized the paraphrasing of the title for the well-loved, Canadian movie, “I heard the mermaids singing.” In this case, it’s all about protein folding and data sonification (from an Oct. 20, 2016 news item on phys.org),

Transforming data about the structure of proteins into melodies gives scientists a completely new way of analyzing the molecules that could reveal new insights into how they work – by listening to them. A new study published in the journal Heliyon shows how musical sounds can help scientists analyze data using their ears instead of their eyes.

The researchers, from the University of Tampere in Finland, Eastern Washington University in the US and the Francis Crick Institute in the UK, believe their technique could help scientists identify anomalies in proteins more easily.

An Oct. 20, 2016 Elsevier Publishing press release on EurekAlert, which originated the news item, expands on the theme,

“We are confident that people will eventually listen to data and draw important information from the experiences,” commented Dr. Jonathan Middleton, a composer and music scholar who is based at Eastern Washington University and in residence at the University of Tampere. “The ears might detect more than the eyes, and if the ears are doing some of the work, then the eyes will be free to look at other things.”

Proteins are molecules found in living things that have many different functions. Scientists usually study them visually and using data; with modern microscopy it is possible to directly see the structure of some proteins.

Using a technique called sonification, the researchers can now transform data about proteins into musical sounds, or melodies. They wanted to use this approach to ask three related questions: what can protein data sound like? Are there analytical benefits? And can we hear particular elements or anomalies in the data?

They found that a large proportion of people can recognize links between the melodies and more traditional visuals like models, graphs and tables; it seems hearing these visuals is easier than they expected. The melodies are also pleasant to listen to, encouraging scientists to listen to them more than once and therefore repeatedly analyze the proteins.

The sonifications are created using a combination of Dr. Middleton’s composing skills and algorithms, so that others can use a similar process with their own proteins. The multidisciplinary approach – combining bioinformatics and music informatics – provides a completely new perspective on a complex problem in biology.

“Protein fold assignment is a notoriously tricky area of research in molecular biology,” said Dr. Robert Bywater from the Francis Crick Institute. “One not only needs to identify the fold type but to look for clues as to its many functions. It is not a simple matter to unravel these overlapping messages. Music is seen as an aid towards achieving this unraveling.”

The researchers say their molecular melodies can be used almost immediately in teaching protein science, and after some practice, scientists will be able to use them to discriminate between different protein structures and spot irregularities like mutations.

Proteins are the first stop, but our knowledge of other molecules could also benefit from sonification; one day we may be able to listen to our genomes, and perhaps use this to understand the role of junk DNA [emphasis mine].

About 97% of our DNA (deoxyribonucleic acid) has been known for some decades as ‘junk DNA’. In roughly 2012, that was notion was challenged as Stephen S. Hall wrote in an Oct. 1, 2012 article (Hidden Treasures in Junk DNA; What was once known as junk DNA turns out to hold hidden treasures, says computational biologist Ewan Birney) for Scientific American.

Getting back to  2016, here’s a link to and a citation for ‘protein singing’,

Melody discrimination and protein fold classification by  Robert P. Bywater, Jonathan N. Middleton. Heliyon 20 Oct 2016, Volume 2, Issue 10 DOI: 10.1016/j.heliyon.2016.e0017

This paper is open access.

Here’s what the proteins sound like,

Supplementary Audio 3 for file for Supplementary Figure 2 1r75 OHEL sonification full score. [downloaded from the previously cited Heliyon paper]

Joanna Klein has written an Oct. 21, 2016 article for the New York Times providing a slightly different take on this research (Note: Links have been removed),

“It’s used for the concert hall. It’s used for sports. It’s used for worship. Why can’t we use it for our data?” said Jonathan Middleton, the composer at Eastern Washington University and the University of Tampere in Finland who worked with Dr. Bywater.

Proteins have been around for billions of years, but humans still haven’t come up with a good way to visualize them. Right now scientists can shoot a laser at a crystallized protein (which can distort its shape), measure the patterns it spits out and simulate what that protein looks like. These depictions are difficult to sift through and hard to remember.

“There’s no simple equation like e=mc2,” said Dr. Bywater. “You have to do a lot of spade work to predict a protein structure.”

…

Dr. Bywater had been interested in assigning sounds to proteins since the 1990s. After hearing a song Dr. Middleton had composed called “Redwood Symphony,” which opens with sounds derived from the tree’s DNA, he asked for his help.

Using a process called sonification (which is the same thing used to assign different ringtones to texts, emails or calls on your cellphone) the team took three proteins and turned their folding shapes — a coil, a turn and a strand — into musical melodies. Each shape was represented by a bunch of numbers, and those numbers were converted into a musical code. A combination of musical sounds represented each shape, resulting in a song of simple patterns that changed with the folds of the protein. Later they played those songs to a group of 38 people together with visuals of the proteins, and asked them to identify similarities and differences between them. The two were surprised that people didn’t really need the visuals to detect changes in the proteins.

…

Plus, I have more about data sonification in a Feb. 7, 2014 posting regarding a duet based on data from Voyager 1 & 2 spacecraft.

Finally, I hope my next Steep project will include  sonification of data on gold nanoparticles. I will keep you posted on any developments.

Self-assembling protein inspires University of Montreal’s researchers to smaller efforts

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Protein folding doesn’t seem all that exciting to me and the notion that it might lead to self-assembled, living machines isn’t all that new (see my May 31, 2012 posting about a Living Foundries project). So the June 10, 2012 news item on Nanowerk left me with a flat feeling, initially,

Enabling bioengineers to design new molecular machines for nanotechnology applications is one of the possible outcomes of a study by University of Montreal researchers that was published in Nature Structural and Molecular Biology today (“Visualizing transient protein folding intermediates by tryptophan scanning mutagenesis” [behind a paywall]). The scientists have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer’s and Parkinson’s, which are caused by errors in assembly.

“In order to survive, all creatures, from bacteria to humans, monitor and transform their environments using small protein nanomachines made of thousands of atoms,” explained the senior author of the study, Prof. Stephen Michnick of the university’s department of biochemistry. “For example, in our sinuses, there are complex receptor proteins that are activated in the presence of different odor molecules. Some of those scents warn us of danger; others tell us that food is nearby.” Proteins are made of long linear chains of amino acids, which have evolved over millions of years to self-assemble extremely rapidly – often within thousandths of a split second – into a working nanomachine.

My ears pricked up when the talk turned to capturing images of action, which occurs in a “fleetingly short time,”

“To understand how a protein goes from a linear chain to a unique assembled structure, we need to capture snapshots of its shape at each stage of assembly said Dr. Alexis Vallée-Bélisle, first author of the study. “The problem is that each step exists for a fleetingly short time and no available technique enables us to obtain precise structural information on these states within such a small time frame. We developed a strategy to monitor protein assembly by integrating fluorescent probes throughout the linear protein chain so that we could detect the structure of each stage of protein assembly, step by step to its final structure.” The protein assembly process is not the end of its journey, as a protein can change, through chemical modifications or with age, to take on different forms and functions. “Understanding how a protein goes from being one thing to becoming another is the first step towards understanding and designing protein nanomachines for biotechnologies such as medical and environmental diagnostic sensors, drug synthesis or delivery,” Vallée-Bélisle said.

Here’s an image of protein self-assembly from the University of Montreal (Université de Montréal) website (Montréal, Québec, Canada),

Vallée-Bélisle and Michnick have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer's and Parkinson's, which are caused by errors in assembly. Here shown are two different assembly stages (purple and red) of the protein ubiquitin and the fluorescent probe used to visualize these stage (tryptophan: see yellow). Credit: Peter Allen

I would have liked a little more detail (e.g. how little time is there to capture the images?) but there isn’t always time either for the people who write these news releases or for me to follow up with questions. Given the huge political unrest amongst students over the proposed tuition fees and the Québec government’s attempts (sometimes described as draconian) to impose order, I’m impressed this news release was pulled together.

Folding, origami, and shapeshifting and an article with over 50,000 authors

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I’m on a metaphor kick these days so here goes, origami (Japanese paper folding), and shapeshifting are metaphors used to describe a certain biological process that nanoscientists from fields not necessarily associated with biology find fascinating, protein folding.

Origami

Take for example a research team at the California Institute of Technology (Caltech) working to exploit the electronic properties of carbon nanotubes (mentioned in a Nov. 9, 2010 news item on Nanowerk). One of the big issues is that since all of the tubes in a sample are made of carbon getting one tube to react on its own without activating the others is quite challenging when you’re trying to create nanoelectronic circuits. The research team decided to use a technique developed in a bioengineering lab (from the news item),

DNA origami is a type of self-assembled structure made from DNA that can be programmed to form nearly limitless shapes and patterns (such as smiley faces or maps of the Western Hemisphere or even electrical diagrams). Exploiting the sequence-recognition properties of DNA base paring, DNA origami are created from a long single strand of viral DNA and a mixture of different short synthetic DNA strands that bind to and “staple” the viral DNA into the desired shape, typically about 100 nanometers (nm) on a side.

Single-wall carbon nanotubes are molecular tubes composed of rolled-up hexagonal mesh of carbon atoms. With diameters measuring less than 2 nm and yet with lengths of many microns, they have a reputation as some of the strongest, most heat-conductive, and most electronically interesting materials that are known. For years, researchers have been trying to harness their unique properties in nanoscale devices, but precisely arranging them into desirable geometric patterns has been a major stumbling block.

…

… To integrate the carbon nanotubes into this system, the scientists colored some of those pixels anti-red, and others anti-blue, effectively marking the positions where they wanted the color-matched nanotubes to stick. They then designed the origami so that the red-labeled nanotubes would cross perpendicular to the blue nanotubes, making what is known as a field-effect transistor (FET), one of the most basic devices for building semiconductor circuits.

Although their process is conceptually simple, the researchers had to work out many kinks, such as separating the bundles of carbon nanotubes into individual molecules and attaching the single-stranded DNA; finding the right protection for these DNA strands so they remained able to recognize their partners on the origami; and finding the right chemical conditions for self-assembly.

After about a year, the team had successfully placed crossed nanotubes on the origami; they were able to see the crossing via atomic force microscopy. These systems were removed from solution and placed on a surface, after which leads were attached to measure the device’s electrical properties. When the team’s simple device was wired up to electrodes, it indeed behaved like a field-effect transistor

Shapeshifting

For another more recent example (from an August 5, 2010 article on physorg.com by Larry Hardesty,  Shape-shifting robots),

By combining origami and electrical engineering, researchers at MIT and Harvard are working to develop the ultimate reconfigurable robot — one that can turn into absolutely anything. The researchers have developed algorithms that, given a three-dimensional shape, can determine how to reproduce it by folding a sheet of semi-rigid material with a distinctive pattern of flexible creases. To test out their theories, they built a prototype that can automatically assume the shape of either an origami boat or a paper airplane when it receives different electrical signals. The researchers reported their results in the July 13 issue of the Proceedings of the National Academy of Sciences.

As director of the Distributed Robotics Laboratory at the Computer Science and Artificial Intelligence Laboratory (CSAIL), Professor Daniela Rus researches systems of robots that can work together to tackle complicated tasks. One of the big research areas in distributed robotics is what’s called “programmable matter,” the idea that small, uniform robots could snap together like intelligent Legos to create larger, more versatile robots.

Here’s a video from this site at MIT (Massachusetts Institute of Technology) describing the process,

Folding and over 50, 000 authors

With all this I’ve been leading up to a fascinating project, a game called Foldit, that a team from the University of Washington has published results from in the journal Nature (Predicting protein structures with a multiplayer online game), Aug. 5, 2010.

With over 50,000 authors, this study is a really good example of citizen science (discussed in my May 14, 2010 posting and elsewhere here) and how to use games to solve science problems while exploiting a fascination with folding and origami. From the Aug. 5, 2010 news item on Nanowerk,

The game, Foldit, turns one of the hardest problems in molecular biology into a game a bit reminiscent of Tetris. Thousands of people have now played a game that asks them to fold a protein rather than stack colored blocks or rescue a princess.

…

Scientists know the pieces that make up a protein but cannot predict how those parts fit together into a 3-D structure. And since proteins act like locks and keys, the structure is crucial.

At any moment, thousands of computers are working away at calculating how physical forces would cause a protein to fold. But no computer in the world is big enough, and computers may not take the smartest approach. So the UW team tried to make it into a game that people could play and compete. Foldit turns protein-folding into a game and awards points based on the internal energy of the 3-D protein structure, dictated by the laws of physics.

Tens of thousands of players have taken the challenge. The author list for the paper includes an acknowledgment of more than 57,000 Foldit players, which may be unprecedented on a scientific publication.

…

“It’s a new kind of collective intelligence, as opposed to individual intelligence, that we want to study,”Popoviç [principal investigator Zoran Popoviç, a UW associate professor of computer science and engineering] said. “We’re opening eyes in terms of how people think about human intelligence and group intelligence, and what the possibilities are when you get huge numbers of people together to solve a very hard problem.”

There’s a more at Nanowerk including a video about the gamers and the scientists. I think most of us take folding for granted and yet it stimulates all kinds of research and ideas.

Poetry, molecular biophysics and innovation in Canada

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There’s an interesting story by Karen Hopkin (Carpe Datum)  in the latest The Scientist newsletter about Gregory Petsko, a would-be student of epic poetry who changed his field of studies to molecular biophysics as he made his way to a Rhodes scholarship at Oxford. From Carpe Datum,

With his heart set on the study of epic poetry, Petsko arranged to work with Maurice Bowra, a preeminent classicist, and set sail for England. “Back then, all the Rhodes scholars traveled over on the Queen Elizabeth, which took 8 days,” he says. “And sometime while I was out over the Atlantic, Maurice Bowra died.” Not sure how to proceed, Petsko phoned Princeton and spoke to the head of the lab where he’d worked part-time to earn a few bucks. “He told me to go over to David Phillips’s lab and get a degree in molecular biophysics,” says Petsko. “And it was the best thing that ever happened to me.”

…

“For me, structure is just a means to an end. That end is function. I care about function,” he says. “I want to know how things work.”

“Greg never loses sight of the big picture. For him, it’s ultimately about the biology,” says former postdoc Ann Stock, an HHMI investigator at the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School. “In the field of structural biology, that hasn’t always been true. In the early years, many structural biologists focused mostly on the nuts-and-bolts technical aspects of solving three-dimensional structures.” Petsko is proficient when it comes to nuts and bolts, she says, “but he sees them as tools that allow him to explore the biology of proteins.”

I find it interesting that Petsko is well grounded in the humanities as there is a longstanding argument that an education in the humanities and/or liberal arts is a “big picture” education. Petsko’s discoveries include the TIM barrel,

“It’s like an alpha helix or a beta-pleated sheet: the TIM barrel is a protein fold that basically implies function,” says [Jan] Westpheling [geneticist at University of Georgia]. “And Greg discovered it. This was a profound contribution in the days when people were just beginning to understand the three-dimensional structure of proteins.”

If you’re interested in more about how scientists think and work, please do read Hopkin’s story as I’m now switching gears to Rob Annan’s (Don’t leave Canada behind blog) latest post, Innovation isn’t just about science funding.

Rob raises a number of points about innovation in Canada, along with this one (from the post),

Expecting researchers to produce innovative research and to translate it into the broader world is unrealistic. And giving more money to researchers isn’t going to change that.

Much of the discussion about Canada’s lack of innovation is focused on how money can be made from research. Scientists are quite innovative in their research; the problem, from the government’s perspective, lies in bringing the research to market. Back to Rob,

… Unlike scientific research, social and commercial innovation isn’t a relatively linear process you can lay out in five year funding applications. It doesn’t require a highly-specialized skill set. It requires a broad skill set that involves creative thinking, communication skills, problem-solving, critical thinking, and cultural and civic understanding – all of which need to be applied to the varied stages of innovation development.

These are the attributes of successful entrepreneurs. These are also the attributes of a liberal arts and science education.

You might say that Petsko embodies “the attributes of a liberal arts and science education,” although as far as I know he’s not an entrepreneur.  Rob expands on the notion of “big picture” education,

Even a who’s-who of Canadian high-tech CEOs have made an explicit case for the importance of liberal arts and science graduates in their industries.

Yes, we need to fund scientific research to ensure that we have a deep pool of innovation from which to draw. But translating this research into world-leading social or commercial innovation won’t happen if we leave it strictly to the scientists. Individuals trained in the social sciences and humanities bring an essential skill set to the process, and we neglect funding these areas at our competitive peril.

Thank you, Rob. It’s always good when someone who’s a scientist makes these kinds of comments as someone with a liberal arts/social science/humanities background could be accused of being self-serving.

While the  Petsko story doesn’t perfectly illustrate Rob’s points, it does hint at the importance of broad-based thinking for breakthroughs and, ultimately, innovation. I’d add one item to Rob’s list of skills, risktaking.

I do have a few questions but I’m going to take those to Rob’s comments section.