…
In what fields would APM cause the most pronounced economic disruption and the collapse of global supply chains to more local chains?

The digital revolution had far-reaching effects on information industries. APM-based production promises to have similarly far-reaching effects, but transposed into the world of physical products. In thinking about implications for international trade and economic organization, three aspects should be kept in mind: a shift from scarce to common raw materials, a shift from long supply chains to more direct paths from raw materials to finished products, and a shift toward flexible, localized manufacturing based on production systems with capabilities that are comparable on-demand printing. This is enough to at least suggest the scope of the changes to expect from a mature form of APM-based production — which again is a clear prospect but emphatically not around the corner.
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-Posted by Stephanie C

(credit: Mary Leonard, University of Pennsylvania Biomedical Art & Design)

Research into using nanotechnology for improved drug delivery continues to advance as current nanoparticle technology is combined with increasingly more sophisticated biotechnology. One major problem with using nanoparticles for targeted drug delivery is that the patient’s immune system often clears the particle before they can be effective. A new approach uses a peptide derived from an important immune system molecule to fool the immune system. A commentary accompanying the publication (abstract) of the research in Science describes how short peptides from a human protein called CD47, which tells important immune system cells that cells or particles bearing the protein are human, not foreign, were used as a “passport” to get nanoparticles past the immune system. Additional details are supplied in a University of Pennsylvania news release “Penn Researchers Develop Protein ‘Passport’ That Helps Nanoparticles Get Past Immune System“:

… The research was conducted by professor Dennis Discher, graduate students Pia Rodriguez, Takamasa Harada, David Christian and Richard K. Tsai and postdoctoral fellow Diego Pantano … “From your body’s perspective,” Rodriguez said, “an arrowhead a thousand years ago and a pacemaker today are treated the same — as a foreign invader.

“We’d really like things like pacemakers, sutures and drug-delivery vehicles to not cause an inflammatory response from the innate immune system.”

The innate immune system attacks foreign bodies in a general way. Unlike the learned response of the adaptive immune system, which includes the targeted antibodies that are formed after a vaccination, the innate immune system tries to destroy everything it doesn’t recognize as being part of the body.

This response has many cellular components, including macrophages — literally “big eaters” — that find, engulf and destroy invaders. Proteins in blood serum work in tandem with macrophages; they adhere to objects in the blood stream and draw macrophages’ attention. If the macrophage determines these proteins are stuck to a foreign invader, they will eat it or signal other macrophages to form a barrier around it.

Drug-delivery nanoparticles naturally trigger this response, so researchers’ earlier attempts to circumvent it involved coating the particles with polymer “brushes.” These brushes stick out from the nanoparticle and attempt to physically block various blood serum proteins from sticking to its surface.

However, these brushes only slow down the macrophage-signaling proteins, so Discher and colleagues tried a different approach: Convincing the macrophages that the nanoparticles were part of the body and shouldn’t be cleared.

In 2008, Discher’s group showed that the human protein CD47, found on almost all mammalian cell membranes, binds to a macrophage receptor known as SIRPa in humans. Like a patrolling border guard inspecting a passport, if a macrophage’s SIRPa binds to a cell’s CD47, it tells the macrophage that the cell isn’t an invader and should be allowed to proceed on.

“There may be other molecules that help quell the macrophage response,” Discher said. “But human CD47 is clearly one that says, ‘Don’t eat me’.”

Since the publication of that study, other researchers determined the combined structure of CD47 and SIRPa together. Using this information, Discher’s group was able to computationally design the smallest sequence of amino acids that would act like CD47. This “minimal peptide” would have to fold and fit well enough into the receptor of SIRPa to serve as a valid passport.

After chemically synthesizing this minimal peptide, Discher’s team attached it to conventional nanoparticles that could be used in a variety of experiments.

“Now, anyone can make the peptide and put it on whatever they want,” Rodriguez said.

The research team’s experiments used a mouse model to demonstrate better imaging of tumors and as well as improved efficacy of an anti-cancer drug-delivery particle.

As this minimal peptide might one day be attached to a wide range of drug-delivery vehicles, the researchers also attached antibodies of the type that could be used in targeting cancer cells or other kinds of diseased tissue. Beyond a proof of concept for therapeutics, these antibodies also served to attract the macrophages’ attention and ensure the minimal peptide’s passport was being checked and approved.

“We’re showing that the peptide actually does inhibit the macrophage’s response,” Discher said. “We force the interaction and then overwhelm it.”

The test of this minimal peptide’s efficacy was in mice that were genetically modified so their mac[r]ophages had SIRPa receptors similar to the human version. The researchers injected two kinds of nanoparticles — ones carrying the peptide passport and ones without — and then measured how fast the mice’s immune systems cleared them.

“We used different fluorescent dyes on the two kinds of nanoparticles, so we could take blood samples every 10 minutes and measure how many particles of each kind were left using flow cytometry,” Rodriguez said. “We injected the two particles in a 1-to-1 ratio and 20-30 minutes later, there were up to four times as many particles with the peptide left.”

Even giving therapeutic nanoparticles an additional half-hour before they are eaten by macrophages could be a major boon for treatments. Such nanoparticles might need to make a few trips through the macrophage-heavy spleen and liver to find their targets, but they shouldn’t stay in the body indefinitely. Other combinations of exterior proteins might be appropriate for more permanent devices, such as pacemaker leads, enabling them to hide from the immune system for longer periods of time.

While more research is necessary before such applications become a reality, reducing the peptide down to a sequence of only a few amino acids was a critical step. The relative simplicity of this passport molecule to be more easily synthesized makes it a more attractive component for future therapeutics. …

A very interesting feature of this work is the computational identification of a small structure, in this case a peptide, that can substitute for a crucial part of the function of a large biological system (phagocytic cells to recognize non-self). We should probably expect to see this strategy often as nanomedicine evolves from predominantly biotechnology toward more machine-like advanced nanotechnology.
—James Lewis, PhD

This illustration shows the structure of the molecular motors. (Credit: Saw-Wai Hla)

An international team of scientists has taken the next step in creating nanoscale machines by designing a multi-component molecular motor that can be moved clockwise and counterclockwise.

Although researchers can rotate or switch individual molecules on and off, the new study is the first to create a stand-alone molecular motor that has multiple parts, said Saw-Wai Hla, an Ohio University professor of physics and astronomy who led the study with Christian Joachim of A*Star in Singapore and CEMES/CNRS in France and Gwenael Rapenne of CEMES/CNRS.

It’s an essential step in creating nanoscale devices—quantum machines that operate on different laws of physics than classical machines—that scientists envision could be used for everything from powering quantum computers to sweeping away blood clots in arteries.

In the study, published in Nature Nanotechnology [abstract], the scientists demonstrated that they could control the motion of the motor with energy generated by electrons from a scanning tunneling microscope tip. The motor is about 2 nanometers in length and 1 nanometer high and was constructed on a gold crystal surface. [Watch an animation of the motor at the journal's website here. Credit: F. Ample and C. Joachim. (Scroll down to "Supplementary information" for links to the two animations.)]

At a temperature of minus 315 degrees Fahrenheit, the motor could move independently through thermal excitation. When scientists cooled the sample to minus 450 degrees, the motor stopped rotating. The researchers selectively applied electron energy to different parts of the motor to prompt it to move clockwise and counterclockwise.

“If we want to build an actual device based on this motor, we would install electrodes on the surface to create an energy source,” Hla said.

To construct the molecular motor, the scientific team designed a stationary base of atoms that is connected to an upper moving part by one atom of ruthenium, which serves as the “ball bearing.” The upper piece of the motor features five arms made of iron atoms. The researchers made one arm shorter than the others to be able to track the motion of the machine. The entire device is held upright by using sulfur as an “atomic glue” to secure the motor to the gold surface, Hla explained.

The scientists now plan to use this model to build more complex machines with components that could be automated, Hla said.

One of the three corresponding authors is Christian Joachim, winner of the 2005 Foresight Nanotech Institute Feynman Prize for Theoretical work and one of three winners of the 1997 Foresight Nanotech Institute Feynman Prize for Experimental work.

The molecular motor consists of a single ruthenium atom bearing connecting a tripodal stator to a five-arm rotor. to help detect the motion of the rotor, the five arms are not all equivalent. The centner of the rotor is a cyclopentadiene, one short arms is merely a toluene, while the other four long arms each comprise a phenyl group connected to a ferrocene (two cyclopentadienyl rings sandwiching an iron atom). The ferrocene groups act as reversible electron relays. The four ferrocene end groups enable control of rotation by four nanoelectrodes. The tripodal stator comprises a boron atom connected to three indazolyl groups, each with a thioether foot that binds via a sulfur atom to the gold surface upon which the motor sits.

The motor was imaged using a scanning tunneling microscope (STM) under ultra high vacuum conditions (UHV). For some samples a large bias voltage pulse was used to remove the top (rotor) part of the motor, revealing the tripod stator positioned with each leg along a [211] surface direction of the Au(111) surface. At 80 K the image of the intact motor shows a uniform circle due to the free rotation of the rotor. At 4.6 K rotation has been stopped so that the asymmetric five-lobe structure of the rotor is visible, with four long arms and one short arm.

After positioning the tungsten STM tip above the center of the rotor and then gradually increasing the voltage, rotation was observed at 0.6 V due to inelastic electron tunneling energy transfer. Stepwise rotation was achieved at 4.6 K by placing the STM tip over the molecule at a fixed height for an excitation period of less than one second. The direction of rotation was determined by where the STM tip was placed: predominantly clockwise if electrons were passing through the truncated arm, and mostly counterclockwise if electron excitation was via a ferrocene arm. The authors point out that the tripodal stator lifts the rotor high enough about the gold surface so that the surface does not influence the rotation. They present semi-empirical and density functional theory calculations to explain the detailed rotational mechanisms of the motor. The results show that asymmetries in rotational energy potential lead to the observed rotations by selective excitation of different subunits of the motor. They believe this understanding “will further accelerate the development of complex and automated nanomachinery that can be operated on a material surface.”

The combination of a multicomponent molecular motor and detailed theoretical analysis to elucidate the mechanisms responsible for the action of the motor raises the hope that this work will indeed further accelerate development of complex automated molecular machinery.
—James Lewis, PhD

Comparison of computational models with experimentally determined structure: design model (left) and NMR structure (right). Credit: Nobuyasu Koga et al./Nature)

Yet another milestone along the protein design molecular engineering path to advanced nanotechnology has been reached, thanks to the efforts of the laboratory of David Baker, one of the 2004 winners of the Foresight Feynman Prize in Nanotechnology for Theoretical work. From KurzweilAI “How to design proteins from scratch“:

… By following a set of rules, they designed five proteins from scratch that fold reliably into predicted conformations. In a blind test, the team showed that the synthesized proteins closely match the predicted structures.

“What you have now is a flexible set of building blocks for nanoscale assembly,” says Jeremy England, a molecular biophysicist at the Massachusetts Institute of Technology in Cambridge, who was not involved in the work. …

More detail is given in a commentary in Nature, the journal in which the research was published “Proteins made to order: Researchers design proteins from scratch with predictable structures“:.

… Baker’s proteins are in a sense “platonic ideals”, he says: simple backbone constructs with every amino acid optimized to fold into the prescribed, stable structure. In this way they differ from natural proteins, whose folded structures represent a compromise between the competing requirements of optimum folding and biological function, leading to “frustrated” parts of the sequence that may be essential for function but are destabilizing to the fold. As evidence of their stability, the designed proteins melt at about 100 °C, Koga says, compared to 40–50 °C for a natural protein. …

The best summary of the significance of this result is given by the authors in the conclusion of their paper (reference numbers omitted from quotation):

The design principles and methodology we have described should allow the ready design of a wide range of robust and stable protein building blocks for the next generation of engineered functional proteins. Almost all protein design and engineering efforts so far have repurposed naturally occurring proteins that evolved for some other, often unrelated, function. It should now become possible to custom-design protein scaffolds ideal for the desired function, and to build larger assemblies and materials from robust ideal building blocks.

From the standpoint of advanced nanotechnology/molecular manufacturing, the “build larger assemblies” part is especially interesting. The abstract of the research is available on the journal web site, and the authors have made a full text PDF available on the Baker lab web site.
—James Lewis, PhD

Noncontact AFM with a carbon monoxide-functionalized tip was used to image C-C bonds of different length and bond order in a nanographene molecule. The molecules used were synthesized by Centro de Investigacion en Quimica Bioloxica e Materiais Moleculares (CIQUS) at the Universidade de Santiago de Compostela and Centre National de la Recherche Scientifique (CNRS) in Toulouse. (Credit: IBM Research-Zurich)

Scanning probe microscopy (SPM) is one of the principal paths to atomically precise manufacturing (molecular manufacturing). One of the varieties of SPM that shows great promise is noncontact atomic force microscopy (NC-AFM). In a significant milestone, a team of scientists at IBM has greatly expanded the capabilities of NC-AFM by providing unprecedented information about the length and strength of individual chemical bonds within molecules. A hat tip to ScienceDaily for reprinting this IBM press release “IBM Scientists First to Distinguish Individual Molecular Bonds“:

IBM (NYSE: IBM) scientists have been able to differentiate the chemical bonds in individual molecules for the first time using a technique known as noncontact atomic force microscopy (AFM).

The results push the exploration of using molecules and atoms at the smallest scale and could be important for studying graphene devices, which are currently being explored by both industry and academia for applications including high-bandwidth wireless communication and electronic displays.

“We found two different contrast mechanisms to distinguish bonds. The first one is based on small differences in the force measured above the bonds. We expected this kind of contrast but it was a challenge to resolve,” said IBM scientist Leo Gross. “The second contrast mechanism really came as a surprise: Bonds appeared with different lengths in AFM measurements. With the help of ab initio calculations we found that the tilting of the carbon monoxide molecule at the tip apex is the cause of this contrast.”

As reported in the cover story of the September 14th issue of Science magazine [abstract], IBM Research scientists imaged the bond order and length of individual carbon-carbon bonds in C₆₀, also known as a buckyball for its football shape and two planar polycyclic aromatic hydrocarbons (PAHs), which resemble small flakes of graphene. The PAHs were synthesized by Centro de Investigacion en Quimica Bioloxica e Materiais Moleculares (CIQUS) at the Universidade de Santiago de Compostela and Centre National de la Recherche Scientifique (CNRS) in Toulouse.

The individual bonds between carbon atoms in such molecules differ subtly in their length and strength. All the important chemical, electronic, and optical properties of such molecules are related to the differences of bonds in the polyaromatic systems. Now, for the first time, these differences were detected for both individual molecules and bonds. This can increase basic understanding at the level of individual molecules, important for research on novel electronic devices, organic solar cells, and organic light-emitting diodes (OLEDs). In particular, the relaxation of bonds around defects in graphene as well as the changing of bonds in chemical reactions and in excited states could potentially be studied.

As in their earlier research (Science 2009, 325, 1110, abstract) the IBM scientists used an atomic force microscope (AFM) with a tip that is terminated with a single carbon monoxide (CO) molecule. This tip oscillates with a tiny amplitude above the sample to measure the forces between the tip and the sample, such as a molecule, to create an image. The CO termination of the tip acts as a powerful magnifying glass to reveal the atomic structure of the molecule, including its bonds. This made it possible to distinguish individual bonds that differ only by 3 picometers or 3 × 10^-12 meters, which is about one-hundredth of an atom’s diameter. …

The images made soon after AFM was invented in 1986 did not achieve atomic resolution, so the achievement of picometer-level resolution is indeed an impressive accomplishment. It will be interesting to see if greater precision in imaging will lead to greater precision in manipulation of atoms and individual chemical bonds.
—James Lewis, PhD

Predicted structure of the cyclic nonamer proposed by the theorists, shown to match the actual folded structure with remarkable accuracy (credit: Lawrence Berkeley National Laboratory).

Peptoids are chemical cousins of proteins that present opportunities for molecular engineering comparable to but different from those presented by biomolecular systems (reviewed by Drexler here). Progress toward rational design of peptoids has been reported by a team of scientists at New York University, Lawrence Berkeley National Laboratory, Simprota Corporation, Stony Brook University, and Temple University. A hat tip to KurzweilAI.net for describing this news release from Lawrence Berkeley National Laboratory “Form, Function and Folding: In collaboration with Berkeley Lab, a team of scientists move toward rational design of artificial proteins“:

In the world of proteins, form defines function. Based on interactions between their constituent amino acids, proteins form specific conformations, folding and twisting into distinct, chemically directed shapes. The resulting structure dictates the proteins’ actions; thus accurate modeling of structure is vital to understanding functionality.

Peptoids, the synthetic cousins of proteins, follow similar design rules. Less vulnerable to chemical or metabolic breakdown than proteins, peptoids are promising for diagnostics, pharmaceuticals, and as a platform to build bioinspired nanomaterials, as scientists can build and manipulate peptoids with great precision. But to design peptoids for a specific function, scientists need to first untangle the complex relationship between a peptoid’s composition and its function-defining folded structure.

Past efforts to predict protein structure have met with limited success, but now a scientific team led by Glenn Butterfoss, and Barney Yoo, research scientists at New York University, in collaboration with investigators from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), Stony Brook University and Temple University have demonstrated that a computer modeling approach similar to one used to predict protein structures can accurately predict peptoid conformation as well.

The authors describe this accomplishment in a new paper in the Proceedings of the National Academy of Sciences (PNAS) titled, “De novo structure prediction and experimental characterization of folded peptoid oligomers,” [abstract] coauthored by Jonathan Jaworski, Ilya Chorny, Ken Dill, Ronald Zuckermann, Richard Bonneau, Kent Kirshenbaum, and Vincent Voelz.

“Natural selection has engineered protein sequences that can self-assemble into molecular machines with specific functions. Why can’t we do the same with biologically inspired synthetic materials?” Voelz, Principal Investigator with Temple University, explains. …

Together, they proposed a ‘blind structure prediction’ challenge. This self-assessment technique, responsible for the enormous progress in the world of protein structure modeling, allows scientists to test the fidelity of their computational models by predicting the three-dimensional structure of a known molecule and then comparing their proposed structure to the X-ray crystallography results.

An analogous, combined experimental-computational method was employed by the peptoid team in an effort to advance the computational design of peptoid structure. X-ray crystal structures for three peptoid molecules, two small and linear and one larger and cyclical, were simultaneously determined, but not disclosed to the theoretical modelers. The experimentalists then used a combination of two simulation techniques, Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement (QM). REMD can efficiently predict the preferred general conformations, and the QM calculations further refine the conformational prediction. In combination, these two calculations accurately define the physical structures of molecules.

The proposed structural predictions of the peptoid molecules did exceedingly well at calculating the actual folded conformations. The first two blind predictions were calculated for two linear, small N-alkyl and N-aryl peptoid trimers. Of these, the N-aryl peptoid trimer was the best blind prediction, matching the crystal described conformation to within 0.2 Å. The N-alkyl trimer prediction matched less well with the crystal results because of its increased flexibility.

The greater challenge facing the group was structural prediction of the larger, cyclic peptoid nonamer. Six different possible conformations were considered for the final, submitted prediction and the top pick proved to agree best with the crystallography results to an accuracy of 1.0 Å.

This success suggests that reliable structure prediction for complex three-dimensional folds is within reach, an enormous step forward on the path to reliable and efficient computational peptoid design. …

Their success at computational modeling could easily accelerate progress along this path to advanced molecular nanotechnology to determine the potential advantages of such structures. The main caveat is that the largest structure they have worked with so far is made from only nine subunits, so that it will be important to determine how well their computational method works with larger and more varied structures.
—James Lewis, PhD

(Credit: Image courtesy of University of California-Los Angeles)

Early this year we commented on progress in designing an artificial enzyme to catalyze the Diels-Alder reaction, an important cycloaddition reaction in synthetic organic chemistry that had been proposed as one strategy to develop molecular building block for molecular manufacturing. A new understanding of exactly how the Diels-Alder reaction occurs validates computational methods that may lead to the ability to design a protein catalyst for whatever reaction is needed. A hat tip to ScienceDaily for reprinting this UCLA news release “New insights into how the most iconic reaction in organic chemistry really works“:

… Now, Kendall N. Houk, UCLA’s Saul Winstein Professor of Organic Chemistry, and colleagues report exactly how the Diels–Alder reaction occurs. Their research is published this week in the early online edition of the journal Proceedings of the National Academy of Sciences [abstract] and will be published in an upcoming print edition.

“We have examined the molecular dynamics of the Diels–Alder reaction, which has become the most important reaction in synthesis, in detail to understand how it happens,” said Houk, who is a member of the California NanoSystems Institute at UCLA.

Houk and his colleagues created a number of simulations — he calls them short movies — of molecules coming together and reacting. …

“The idea,” Houk said, “is to understand how the reaction happens — not just that A goes to B and B goes to C, but to actually follow how the bonds are forming and how the atoms are moving as these things come together. Using the massive computing power we have now, we get a degree of resolution of the mechanism that was not really possible before. It took a lot of computer time, but as a result, we now have unprecedented insight into how this reaction occurs.”

Organic chemists have argued about this for years: If two bonds form during a reaction, do they form at the same time, or does one form first and then the other?

“We find that for the simplest Diels–Alder cycloaddition, it takes only about five femtoseconds on average between the formation of the two bonds; we consider that as occurring simultaneously,” Houk said. (A femtosecond is approximately one millionth of one billionth of a second.)

Houk’s new PNAS paper is his first in the journal since being elected to the National Academy of Sciences in 2010. The same PNAS issue also features an interview with Houk, who is one of the most prolific chemists in the world and one of the world’s leading physical organic chemists.

“We have studied many different classes of reactions and come up with various kinds of rules for understanding why things happen the way they do,” Houk said in the interview.

He and his colleagues — who include David Baker at the University of Washington, Charles Doubleday at Columbia University and Kersey Black at Claremont McKenna College — use computational methods to better understand basic chemical reactions and to design proteins and enzymes to catalyze chemical reactions. The combination of computational design and molecular biology “leads to a catalyst for whatever reaction is needed, if we can get this all to work properly,” Houk said.

Describing his research to predict the structure of novel proteins that could catalyze specific chemical reactions, he said, “The idea is to design a catalyst for any reaction that’s important for whatever reason — an important drug or a commercial product, for example.” …

Or maybe to design catalysts to attach to specific locations on a DNA origami lattice to accomplish a multistep reaction to synthesize some complex molecular building block?
—James Lewis, PhD

January 11-13, 2013
Crowne Plaza Cabana Hotel, Palo Alto, CA USA

Over 30 speakers will present reviews and research on a wide variety of groundbreaking atomic- and molecular-scale science and technology, interesting intrinsically and for aiding the development of atomically precise technologies, devices and materials. Events will include an opening reception with a special panel discussion on Friday night and the Feynman Prize Awards Banquet on Saturday night.

Conference Co-Chairs
J. Fraser Stoddart, Board of Trustees Professor, Northwestern University
Larry S. Millstein, President, Foresight Institute

Conference Sponsors
The Thiel Foundation
Autodesk

Sessions
Atomic Scale Devices
Chair: John Randall – President, Zyvex Labs
Molecular Machines & Non-Equilibrium Processes
Chair: J. Fraser Stoddart – Board of Trustees Professor of Chemistry, Northwestern University
Self-Organizing & Adaptive Systems
Chair: Lee Cronin – Gardiner Chair of Chemistry, Glasgow University
Commercially Implemented Single Molecule Technologies
Chair: Steve Turner – Founder/CTO, Pacific Biosciences
Computation and Molecular Nanotechnology
Chair: Alexander Wissner-Gross – Harvard and MIT Media Lab

Look for further details on the conference, the speakers and the events in the coming weeks and months. Registration will open in late July or early August.

This is a molecular cage created by designing specialized protein puzzle pieces. Every color represents a separate protein, where cylindrical segments indicate rigid parts and ribbon-like segments indicate flexible parts of each protein chain. The grey sphere in the protein cage was placed there to indicate the empty space in the middle of the container and is not part of the molecular structure. (Credit: Todd Yeates, Yen-Ting Lai/UCLA Chemistry and Biochemistry)

An advance in protein engineering targeted to better drug delivery methods or artificial vaccines is also an important step toward a general capability to build nanostructures by assembling designed protein domains in a designed rigid configuration. A hat tip to ScienceDaily for reprinting this UCLA news release written by Kim DeRose “Building molecular ‘cages’ to fight disease“:

UCLA biochemists have designed specialized proteins that assemble themselves to form tiny molecular cages hundreds of times smaller than a single cell. The creation of these miniature structures may be the first step toward developing new methods of drug delivery or even designing artificial vaccines.

“This is the first decisive demonstration of an approach that can be used to combine protein molecules together to create a whole array of nanoscale materials,” said Todd Yeates, a UCLA professor of chemistry and biochemistry and a member of the UCLA–DOE Institute of Genomics and Proteomics and the California NanoSystems Institute at UCLA.

Published June 1 in the journal Science [abstract], the research could be utilized to create cages from any number of different proteins, with potential applications across the fields of medicine and molecular biology.

UCLA graduate student Yen-Ting Lai, lead author of the study, used computer models to identify two proteins that could be combined to form perfectly shaped three-dimensional puzzle pieces. Twelve of these specialized pieces fit together to create a molecular cage a mere fraction of the size of a virus.

“If you just connect two random proteins together, you expect to get an irregular network,” said Yeates, senior author of the study. “In order to control the geometry, the idea was to make a rigid link holding the two proteins in place as if they were parts of a toy puzzle.”

The specifically designed proteins intermesh to form a hollow lattice that could act as a vessel for drug delivery, he said.

“In principle, it would be possible to attach a recognition sequence for cancer cells on the outside of the cage, with a toxin or some other ‘magic bullet’ contained inside,” said Yeates. “That way, the drug could be delivered directly to certain targets like tumor cells.” …

A second breakthrough

A second paper co-authored by Yeates creates similarly designed molecular cages using multiple copies of the same protein as building blocks. The scientists control the shape of the cage by computing the sequence of amino acids necessary to link the proteins together at the correct angles. The research, also published today in Science [abstract], resulted from a collaboration between the UCLA team and professor David Baker [co-winner of the 2004 Foresight Institute Feynman Prize for Theoretical Molecular Nanotechnology] at the University of Washington.

This alternative method represents a more versatile approach because it requires only one type of protein to form a structure, Yeates said. However, devising different kinds of links between the identical proteins remains a major challenge. Lead author Neil King, a postdoctoral scholar at the University of Washington and a former student of Yeates, took the numerous computer-generated possibilities and tested each version experimentally until he found one which produced the right behavior.

The first paper reported a tetrahedral supramolecular 12-subunit cage about 16 nm in diameter, with an open center 5 nm in diameter. Each subunit comprised a trimer of one protein and a dimer of a different protein, fused together in a specified geometry. The second paper used trimers of a single protein as building blocks:

… to design a 24-subunit, 13-nm diameter complex with octahedral symmetry and a 12-subunit, 11-nm diameter complex with tetrahedral symmetry. The designed proteins assembled to the desired oligomeric states in solution, and the crystal structures of the complexes revealed that the resulting materials closely match the design models. The method can be used to design a wide variety of self-assembling protein nanomaterials.

Taken together, these two papers document a major advance in designing proteins to use as atomically precise building blocks.
—James Lewis, PhD

This illustration shows lithium atoms (red) adhered to a graphene lattice that will produce electricity when bent, squeezed or twisted. Conversely, the graphene will deform when an electric field is applied, opening new possibilities in nanotechnology. Illustration: Mitchell Ong, Stanford School of Engineering

Bulk piezoelectric materials are already used for atomically precise nanopositioning to position the tips of scanning probe microscopes. Would there be any advantages to engineered control of piezoelectrical properties in a two-dimensional material? Currently piezoelectric properties of materials cannot be engineered—it is a property only available in certain 3D crystals. Now calculations have demonstrated that graphene can be made piezoelectric by adsorbing atoms on one surface. A hat tip to Physorg.com for reprinting this Stanford University news release written by Andrew Myers “Straintronics: Engineers create piezoelectric graphene“:

Graphene is a wonder material. It is a one-hundred-times-better conductor of electricity than silicon. It is stronger than diamond. And, at just one atom thick, it is so thin as to be essentially a two-dimensional material. Such promising physics have made graphene the most studied substance of the last decade, particularly in nanotechnology. In 2010, the researchers who first isolated it shared the Nobel Prize.

Yet, while graphene is many things, it is not piezoelectric. Piezoelectricity is the property of some materials to produce electric charge when bent, squeezed or twisted. Perhaps more importantly, piezoelectricity is reversible. When an electric field is applied, piezoelectric materials change shape, yielding a remarkable level of engineering control.

Piezoelectrics have found application in countless devices from watches, radios and ultrasound to the push-button starters on propane grills, but these uses all require relatively large, three-dimensional quantities of piezoelectric materials.

Now, in a paper published in the journal ACS Nano [abstract], two materials engineers at Stanford have described how they have engineered piezoelectrics into graphene, extending for the first time such fine physical control to the nanoscale.

“The physical deformations we can create are directly proportional to the electrical field applied. This represents a fundamentally new way to control electronics at the nanoscale,” said Evan Reed, head of the Materials Computation and Theory Group at Stanford and senior author of the study.

This phenomenon brings new dimension to the concept of ‘straintronics,’ he said, because of the way the electrical field strains—or deforms—the lattice of carbon, causing it to change shape in predictable ways.

“Piezoelectric graphene could provide an unparalleled degree of electrical, optical or mechanical control for applications ranging from touchscreens to nanoscale transistors,” said Mitchell Ong, a post-doctoral scholar in Reed’s lab and first author of the paper.

Using a sophisticated modeling application running on high-performance supercomputers, the engineers simulated the deposition of atoms on one side of a graphene lattice — a process known as doping — and measured the piezoelectric effect.

They modeled graphene doped with lithium, hydrogen, potassium and fluorine, as well as combinations of hydrogen and fluorine and lithium and fluorine on either side of the lattice. Doping just one side of the graphene, or doping both sides with different atoms, is key to the process as it breaks graphene’s perfect physical symmetry, which otherwise cancels the piezoelectric effect.

The results surprised both engineers.

“We thought the piezoelectric effect would be present, but relatively small. Yet, we were able to achieve piezoelectric levels comparable to traditional three-dimensional materials,” said Reed. “It was pretty significant.”

The researchers were further able to fine tune the effect by pattern doping the graphene—selectively placing atoms in specific sections and not others.

“We call it designer piezoelectricity because it allows us to strategically control where, when and how much the graphene is deformed by an applied electrical field with promising implications for engineering,” said Ong.

While the results in creating piezoelectric graphene are encouraging, the researchers believe that their technique might further be used to engineer piezoelectricity in nanotubes and other nanomaterials with applications ranging from electronics, photonics, and energy harvesting to chemical sensing and high-frequency acoustics.

“We’re already looking at new piezoelectric devices based on other 2D and low-dimensional materials, hoping they might open new and dramatic possibilities in nanotechnology,” said Reed.

Could piezoelectric graphene be used with, for example, DNA origami scaffolding to position molecular tools to execute programmed actions? To hear the researchers discussing their work and plans, including possible application to nanomechanical systems, an ACS Nano podcast is available.
—James Lewis, PhD