The Largest Molecule(s)

Had a random thought about this and sought to look it up.
Surprisingly there are various answers given depending on the "largest (X) type form" -- and claims have changed over the years:
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(more at link...)

New Scientist

Daily news

7 January 2011
Tree-like giant is largest molecule ever made

By Djuke Veldhuis

PG5 could store drugs within its complex, tree-like folds

(Image: Angewandte Chemie)

Meet PG5, the largest stable synthetic molecule ever made.

With a diameter of 10 nanometres and a mass equal to 200 million hydrogen atoms, this huge molecule festooned with tree-like appendages, paves the way to sophisticated structures capable of storing drugs within their folds, or bonding to a wide variety of different substances.

Complex macromolecules abound in nature and PG5 is about the same size as tobacco mosaic virus. But making such large molecules in the lab is tough, as they tend to fall apart while they are being made.

“Synthetic chemistry so far was simply not capable of approaching the size range of such functional units,” says Dieter Schlüter at the Swiss Federal Institute of Technology in Zürich. Previously, polystyrene was the largest stable synthetic molecule, at 40 million hydrogen masses.

To create their molecular giant, Schlüter and his colleagues started with standard polymerisation, in which smaller molecules join up to form a long chain. To this carbon and hydrogen backbone, they added branches made of benzene rings and nitrogen, as well as carbon and hydrogen.

They then performed several similar cycles, adding sub-branches to each existing branch, to build tree-like structures. The result was PG5. In total, the whole synthesis required 170,000 bond formations, Schlüter says.
Outrageous trick

Klaus Mullen of the Max Planck Institute for Polymer Research in Mainz, Germany, is impressed by the feat and calls it an “outrageous” trick.

To synthesise PG5, Schlüter combined standard polymerisation reactions, which assemble small molecules into a long chain or backbone, with reactions from other areas of organic chemistry which attached groups of atoms to the backbone in a radial fashion.

Schlüter says that because both techniques are standard, his team’s work should encourage other researchers to create synthetic macromolecules that they were previously “not brave enough” to attempt.

He says molecules like PG5 could find applications in delivering drugs, which could either dock to their surface via the different branches, or nestle in the spaces produced by the molecule folding in on itself. “There is not a single entity that can challenge the loading capacity of our PG5,” he says.

Journal reference: Angewandte Chemie, DOI: 10.1002/anie.201005164

https://www.newscientist.com/article/dn19931-tree-like-giant-is-largest-molecule-ever-made/

Macromolecule
https://en.wikipedia.org/wiki/Macromolecule

A macromolecule is a very large molecule, such as protein, commonly created by the polymerization of smaller subunits (monomers). They are typically composed of thousands of atoms or more. The most common macromolecules in biochemistry are biopolymers (nucleic acids, proteins, carbohydrates and polyphenols) and large non-polymeric molecules (such as lipids and macrocycles).[1] Synthetic macromolecules include common plastics and synthetic fibers as well as experimental materials such as carbon nanotubes.[2][3]

Macromolecules often have unusual physical properties that do not occur for smaller molecules.

For example, DNA in a solution can be broken simply by sucking the solution through an ordinary straw because the physical forces on the molecule can overcome the strength of its covalent bonds. The 1964 edition of Linus Pauling's College Chemistry asserted that DNA in nature is never longer than about 5,000 base pairs.[9] This error arose because biochemists were inadvertently breaking their samples into fragments. In fact, the DNA of chromosomes can be hundreds of millions of base pairs long, packaged into chromatin.

Another common macromolecular property that does not characterize smaller molecules is their relative insolubility in water and similar solvents, instead forming colloids. Many require salts or particular ions to dissolve in water. Similarly, many proteins will denature if the solute concentration of their solution is too high or too low.

High concentrations of macromolecules in a solution can alter the rates and equilibrium constants of the reactions of other macromolecules, through an effect known as macromolecular crowding.[10] This comes from macromolecules excluding other molecules from a large part of the volume of the solution, thereby increasing the effective concentrations of these molecules.
Linear biopolymers

All living organisms are dependent on three essential biopolymers for their biological functions: DNA, RNA and proteins.[11] Each of these molecules is required for life since each plays a distinct, indispensable role in the cell.[12] The simple summary is that DNA makes RNA, and then RNA makes proteins.

DNA, RNA, and proteins all consist of a repeating structure of related building blocks (nucleotides in the case of DNA and RNA, amino acids in the case of proteins). In general, they are all unbranched polymers, and so can be represented in the form of a string. Indeed, they can be viewed as a string of beads, with each bead representing a single nucleotide or amino acid monomer linked together through covalent chemical bonds into a very long chain.

In most cases, the monomers within the chain have a strong propensity to interact with other amino acids or nucleotides. In DNA and RNA, this can take the form of Watson-Crick base pairs (G-C and A-T or A-U), although many more complicated interactions can and do occur.

Because of the double-stranded nature of DNA, essentially all of the nucleotides take the form of Watson-Crick base pairs between nucleotides on the two complementary strands of the double-helix.

In contrast, both RNA and proteins are normally single-stranded. Therefore, they are not constrained by the regular geometry of the DNA double helix, and so fold into complex three-dimensional shapes dependent on their sequence. These different shapes are responsible for many of the common properties of RNA and proteins, including the formation of specific binding pockets, and the ability to catalyse biochemical reactions.

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Quantum computer simulates largest molecule yet, sparking hope of future drug discoveries

By Gabriel PopkinSep. 13, 2017 , 1:00 PM

As molecules go, beryllium hydride is puny—just two hydrogen atoms tacked onto a single beryllium atom. But, for the moment, it’s a heavyweight champ: It’s now the largest molecule ever modeled on a quantum computer, an emerging technology that might someday solve problems that stymie ordinary computers. The advance, though still in the realm of what ordinary computers can do, could provide a stepping stone toward a powerful new way to discover new drugs and materials.

“I think it’s very, very promising,” says Marco De Vivo, a theoretical chemist at the Italian Institute of Technology in Genoa, who studies how pharmaceuticals interact with proteins. “They’re pushing the boundaries of what computation today means.”

Physicists and chemists routinely use computers to simulate how atoms and molecules behave. Such simulations require massive amounts of computing power, because interactions between three or more interacting particles quickly become devilishly complex. On top of that, the electrons inside molecules obey the strange laws of quantum mechanics—the theory of the very small—meaning, for example, that it’s impossible to simultaneously pin down an electron’s position and speed. This makes it even harder to calculate the distribution of these electrons within a molecule. Even today’s most powerful supercomputers can simulate molecules only up to a few hundred atoms.

But scientists believe that quantum computers are on track to overtake their classical cousins. As far back as 1981, the Nobel Prize–winning physicist Richard Feynman predicted that computers based on quantum mechanics could simulate large molecules exactly. Whereas an ordinary computer uses bits that can be set to 0 or 1, a quantum computer employs “qubits” that can be set to 0, 1, or 0 and 1 at the same time. These qubits can then be linked together to create a powerful quantum processor, which, in theory, should be able to simulate a molecule far more efficiently than a conventional computer. Many scientists think that revealing new drugs and materials will be the first killer application of future quantum computers, which are being feverishly developed at universities and companies around the world.

Today’s quantum computers, however, are severely limited by the sensitivity of their qubits, whose delicate 0-and-1 quantum states can be disrupted by temperature fluctuations or stray electric or magnetic fields. The more qubits are linked together, the more easily they’re upset. Last year, researchers at Google’s quantum computing lab in Venice, California, used three qubits to calculate the lowest energy electron arrangement of the simplest possible molecule, molecular hydrogen.

IBM’s quantum computing researchers have now raised the bar. The scientists used up to six qubits made of specialized metals called superconductors, which can carry different levels of electric current simultaneously, to analyze hydrogen, lithium hydride, and beryllium hydride (BeH2) molecules. First, they encoded each molecule’s electron arrangement onto the quantum computer. They then used a specialized algorithm to nudge the simulated molecule into lower-energy states, which they measured and encoded onto a conventional computer. They repeated the process until the quantum computer found the molecule’s lowest energy state—an important step in many chemistry applications.

Using this iterative algorithm, IBM’s quantum computer successfully calculated the ground state energy of all three molecules, setting a world record for quantum simulation, the team reports today in Nature.

Because of errors that inevitably creep into quantum calculations, the results are not perfectly accurate, the researchers note. But the demonstration could help chemists better understand known molecules and discover new ones, says Jerry Chow, a physicist in Yorktown Heights, New York, who leads IBM’s quantum computing effort. “We want to make quantum computing something which can extend outside the realm of just simply physics.”

(more at link...)

https://www.sciencemag.org/news/2017/09/quantum-computer-simulates-largest-molecule-yet-sparking-hope-future-drug-discoveries

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Jan Cami on the largest molecule ever found in space
By Beth Lebwohl in Space | September 20, 2010

Astronomers have found a large and very special type of molecule in space.

Astronomers have found a large and very special type of molecule in space. It’s C60, a molecule made of 60 carbon atoms. It’s also called a buckyball or “fullerene” for Buckminster Fuller – this molecule resembles Bucky Fuller’s geodesic domes.

Jan Cami It looks pretty much exactly the same as one of these black and white soccer balls in terms of the structure, but on a microscopic scale.

Jan Cami is an astronomer at the University of Western Ontario and California’s SETI Institute. He and his team reported this discovery in summer 2010, in the journal Science. He said this buckyball is the largest molecule ever found in space – about a nanometer in size – or about one ten-thousandth the thickness of a human hair. They found it by examining light from the vicinity of a planetary nebula – a site of expanding gases surrounding an aging star 6,500 light years away. Cami said buckyballs were first identified in laboratories here on Earth in the 1980s.

Jan Cami: Since then there’s been an entirely new research field that’s built upon the properties of these buckyballs because they have unique physical and chemical and electrical properties. The whole field of nanotechnology on Earth was actually triggered by these buckyballs.

Cami speculated that buckyballs might have been abundant on early Earth, and, because they’re so complex, might even have helped kickstart life on Earth.

Jan Cami: The idea that a lot of astronomers have these days is that if you bring to the early earth some complex molecule, if you can somehow provide seed material in terms of complex molecules to the early Earth, that might actually help kickstart the formation of life of Earth, and even on other planets.

He said that there are some buckyballs, or what scientists also call C60, that occur naturally on Earth. Scientists have found them in the past few decades, after they molecules were first discovered in a laboratory setting.

Jan Cami: We have found very minute quantities of these molecules in specific types of minerals, they also naturally occur – again, in very minute quantities – after lightning strikes.

But scientists now know these molecules are abundant in space. Cami found so many molecules that, if you put them all together, they’d have the same mass as the moon. He added that scientists have persisted in looking for buckyballs in space for decades because they thought there was a good chance the might be there

http://earthsky.org/space/jan-cami-on-largest-space-molecule

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Large Molecule
Analysis of Large Molecule Drugs and Biomarkers

Large molecule work is performed at both our facilities in Lincoln, Nebraska and Zürich, Switzerland. Celerion’s facility in Zürich is one of the largest ligand binding laboratories in the world with more than 25 years’ experience in immunogenicity testing. The team, consisting of over 70 scientists, is renowned for their expertise in immunogenicity testing and has extensive experience in immunoassay capabilities, including method development, validation and production sample analysis for all immunoanalytical technologies.

Immunoanalytical techniques such as ELISA, RIA and Electrochemiluminescence (ECLA) are critical for the analysis of large protein molecules and antibody drugs, as well as biosimilars and biomarkers.

Celerion has developed and validated immunoassay and immunogenicity methods for the analysis of pegylated and non-pegylated therapeutic proteins, peptides, antibodies (intact fragments, single chain, fusion-protein and peptides) and oligonucleotides. The team’s experience with a wide variety of products, including therapeutic proteins (pegylated or nonpegylated), peptides and antibodies, is unparalleled. Full GLP-certified immunoassay capabilities using ELISA, RIA, ECLA, Western blot, and other technologies is provided.

Celerion is expanding the services currently offered with further investments in Luminex technology to enable access to a broad variety of biomarker of effect assays. Panel assays are currently offered at the Zurich facility and based on client demand, coupled with the growth of assays validated to magnetic beads, this powerful technology will be available soon in the Lincoln, Nebraska USA facility.

The list of key pharmacodynamic biomarkers is continually updated, with a recent focus on enhancing diabetes biomarker offerings, including methods for ghrelin, adiponectin, GLP-1, glucagon, c-peptide, IGF-1 and IGFBP-3.

Celerion has the capacity and expertise to help clients achieve their large molecule study timelines.

https://www.celerion.com/service/large-molecule

Cancer and Biological marcomolecules research:
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Biological marcomolecules

SUMMARY

In recent years, scientists have been experimenting with using large molecules called ‘macromolecules’ to target and destroy tumour cells. These macromolecules can disrupt the processes that cancer cells use to survive – for example by stopping them from growing or by flagging their presence to the body’s immune system.

This approach works very well on cancer cells in the laboratory, but unlike conventional ‘small molecule’ treatments like aspirin, it’s really difficult to deliver these molecules to, and then into, the cells where they need to act.

If we could work out ways of delivering these macromolecules to any and every cell in the body, it would not only create a totally new way to treat cancer but would have a huge impact on other diseases too.
BACKGROUND

Biological macromolecules such as proteins, DNA, RNA, siRNA, and antibodies have already been shown to have huge therapeutic potential in cancer and other diseases. They can be engineered to be far more specific and active than current small-molecule therapies.

The challenge is to deliver these macromolecules to, and into, cells in the body, because their size and properties make it difficult to deliver them into the right cells in an active form.

Existing research mostly focuses on targeting the macromolecule to the tissue of interest. We want to look at an alternative approach: delivering a macromolecular drug to all cells, but ensuring that it is only toxic to cancer cells.

Our Grand Challenge is to make what is true today of small molecule drugs into something that also applies to macromolecules: in other words, to develop a macromolecular drug that can be taken as a pill or similar, such that every cell in the body experiences the drug, but only certain cells are killed.
OPPORTUNITIES/BARRIERS

The focus of this challenge is on delivery mechanisms; designing macromolecules so that they can be taken up by a cell’s normal import mechanisms. This strategy of universal delivery is how the cancer drug Gleevec works – it’s a small molecule drug, in tablet form, and although it does affect normal tissue, its major effect is to kill cells carrying the BCR–ABL fusion protein which is exclusively expressed in tumours.

This is an extraordinarily large challenge, as there are many unresolved components of the delivery problem. These include: establishing the optimal delivery method; crossing endothelial barriers (including the blood–brain barrier); pharmacokinetic issues, and a deepened understanding of cell membrane transport mechanisms.

Progress in any or all of these areas will take us closer to overcoming the most important barrier to efficient drug delivery.

https://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-research/grand-challenge-award/challenge7?wssl=1