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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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New open-source software judges accuracy of computer predictions of cancer genetics

Cancers are often made up of many cells which vary genetically to each other. These genetic differences mean the cancer may be particularly susceptible or resistant to a given treatment. As a result, identifying these variations can help clinicians decide which treatment is most likely to be successful for a specific patient.

Because simple clinical methods to test for genetic variation are vulnerable to missing a lot of cell-to-cell variability, recent computer tools have been developed to predict and characterise genetic diversity within clinical tumour samples. However, there is no existing common benchmarking approach to determine the most accurate computational methods.

The study, published in Nature Biotechnology, developed open-source software that can be used to judge the accuracy of computer predictions and establish this benchmark.

The team developed a simulation framework and scoring system to determine how accurately each algorithm predicted various measures of genetic diversity. These included: the proportion of cancerous cells in the tumour sample; the number of genetically different groups of cancerous cells in the tumour sample; the proportion of cells within each of these groups; which genetic mutations were in each group; and the genetic relationship between the groups.

“Our new framework provides a foundation which, over time as it is run against more tumours, will hopefully become a much-needed, unbiased, gold-standard benchmarking tool for assessing models that aim to characterise a tumour’s genetic diversity,” says joint-lead author Maxime Tarabichi, postdoc in the Cancer Genomics Laboratory at the Crick.

The researchers built upon an existing computer software to generate and analyse the 580 predictions in this research, adding new features to the software to create more realistic tumours. This tumour-simulation software and the marking framework are publicly available for other researchers to use either directly or to help develop their own scoring framework.

“Computer simulations in cancer genomics are helping us develop more accurate tools, as we understand where these tools perform well, and where they need improvement,” says author Peter Van Loo, group leader in the Cancer Genomics Laboratory at the Crick. “Further developing these tools, so they more closely match real-life tumours, should ultimately help clinicians better match patients with personalised medicines.”

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Chiton mollusk provides model for new armor design

The motivations for using biology as inspiration to engineering vary based on the project, but for Ling Li, assistant professor of mechanical engineering in the College of Engineering, the combination of flexibility and protection seen in the chiton mollusk was all the motivation necessary.

“The system we’ve developed is based on the chiton, which has a unique biological armor system,” Li said. “Most mollusks have a single rigid shell, such as the abalone, or two shells, such as clams.

But the chiton has eight mineralized plates covering the top of the creature and around its base it has a girdle of very small scales assembled like fish scales, that provide flexibility as well as protection.”

Li’s work, which was featured in the journal Nature Communications Dec. 10, is the result of a collaboration with researchers from various institutions, including the Massachusetts Institute of Technology, the Dana-Farber Cancer Institute at the Harvard Medical School, California State University, Fullerton, the Max Planck Institute of Colloids and Interfaces, Germany, and the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Because the mechanical design of the chiton’s girdle scales had not been studied in-depth before, the team of researchers needed to start with basic material and mechanical analysis with the mollusk before using that information as the bio-inspiration for the engineering research.

“We studied this biological material in a very detailed way. We quantified its internal microstructure, chemical composition, nano-mechanical properties, and three-dimensional geometry. We studied the geometrical variations of the scales across multiple chiton species, and we also investigated how the scales assemble together through 3D tomography analysis,” Li said.

The team then developed a parametric 3D modeling methodology to mimic the geometry of individual scales. They assembled individual scale units on either flat or curved substrates, where the scales’ sizes, orientations, and geometries can also be varied, and used 3D printing to fabricate the bio-inspired scale armor models.

“We produced the chiton scale-inspired scale assembly directly with 3D multi-material printing, which consists of very rigid scales on top of a flexible substrate,” Li explained. With these physical prototypes of controlled specimen geometries and sizes, the team conducted direct mechanical testing on them with controlled loading conditions. This allowed the researchers to understand the mechanisms behind the dual protection-flexibility performance of the biological armor system.

The way the scale armor works is that when in contact with a force, the scales converge inward upon one another to form a solid barrier. When not under force, they can “move” on top of one another to provide varying amounts of flexibility dependent upon their shape and placement.

“The strength comes from how the scales are organized, from their geometry,” Li said. “Reza’s [Mirzaeifar, assistant professor of mechanical engineering] team has done an amazing job by using computational modeling to further reveal how the scale armor becomes interlocked and rigid when the external load reaches a critical value.”

The design of place-specific armor takes into account the size of scales used. Smaller scales, such as those around the girdle of the chiton, are more useful for regions requiring maximum flexibility, while larger scales are used for areas requiring more protection. “Working with Reza, our next step is to expand the space so we can design tailored armor for different body locations.

The flexibility vs. protection needs of the chest, for example, will be different than for the elbow or knee, so we would need to design the scale assembly accordingly in terms of scale geometry, size, orientation, etc.”

The work being featured began with Department of Defense funding when Li was a graduate research assistant at the Massachusetts Institute of Technology. Since he arrived at Virginia Tech in 2017, the work has continued without sponsorship as part of his start-up funding.

“We started with a pretty pure motivation — looking for multifunctional biological materials,” Li said. “We wanted to integrate flexibility and protection and that’s very hard to achieve with synthetic systems. We will continue with our research to explore the design space beyond the original biological model system and conduct testing under different load conditions.”

Li admits the process, which has taken multiple years, is long, but the work is unique in how they’ve approached it from the start as a two-step process in conducting the fundamental biological materials research followed by the bio-inspired research.

“Having that level of familiarity with the subject has been very useful to the design and modeling of the armor,” Li said. “I think this type of bio-inspired armor will represent a significant improvement to what is currently available.”

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