Scientists design new anti-flu virus proteins using computational methods

ScienceDaily (May 14, 2011) — A research article May 12 in Science demonstrates the use of computational methods to design new antiviral proteins not found in nature, but capable of targeting specific surfaces of flu virus molecules.

One goal of such protein design would be to block molecular mechanisms involved in cell invasion and virus reproduction.

Computationally designed, surface targeting, antiviral proteins might also have diagnostic and therapeutic potential in identifying and fighting viral infections.

The lead authors of the study are Sarel J. Fleishman and Timothy Whitehead of the University of Washington (UW) Department of Biochemistry, and Damian C. Ekiert from the Department of Molecular Biology and the Skaggs Institute for Chemical Biology at The Scripps Research Institute. The senior authors are Ian Wilson from Scripps and David Baker from the UW and the Howard Hughes Medical Institute.

The researchers note that additional studies are required to see if such designed proteins can help in diagnosing, preventing or treating viral illness. What the study does suggest is the feasibility of using computer design to create new proteins with antiviral properties.

"Influenza presents a serious public health challenge," the researchers noted, "and new therapies are needed to combat viruses that are resistant to existing anti-viral medications or that escape the body's defense systems."

They focused their attention on the section of the flu virus known as the hemagglutinin stem region. They concentrated on trying to disable this part because of its function in invading the cells of the human respiratory tract.

Their approach was somewhat similar to engineering a small space shuttle with the right configuration and construction, as well as recognizance and interlocking mechanisms, to dock with a troublesome space station and upset its mission. Only these scientists attempted their engineering feat at an atomic and molecular level.

Central to their approach is the ability of biological molecules to recognize certain other molecules or their working parts, and to have an affinity for binding to them at pre-determined locations. This recognition has both physical and chemical bases. Protein-protein interactions underlie many biological activities, including those that disarm and deactivate viruses.

In their report, the researchers described their general computational methods for designing new, tiny protein molecules that could bind to a certain spot on large protein molecules. They took apart some protein structures and watched how these disembodied sections interacted with a target surface. They analyzed particular high-affinity interactions, and used this information to further refine computer-generated designs for interfaces.

"Protein surfaces are never flat, but have many crevices and bulges at the atomic scale," lead author Sarel Fleishman explained. "The challenge is to identify amino acid side chains that would fit perfectly into these surfaces. The fit must be precise both in shape and in other chemical properties such as electrostatic charge. This geometrical and biophysical problem can be computationally solved, but requires large computational resources."

The researchers made use of a peer-to-peer computing platform called Rosetta@Home for going through the hundreds of millions of possible interactions of designed proteins and the surface of hemagglutinin to solve this challenge.

Following optimization, the designed proteins bound hemagglutinin very tightly.

Through this method, the researchers created two designs for new proteins that could bind to a surface patch on the stem of the influenza hemagglutinin from the 1918 H1N1 pandemic flu virus.

The shortcomings of the approach, due to approximations, meant that the researchers started out with 73 possibilities of which just two were successful.

One of the disease-causing characteristics of the influenza hemagglutinin stem is that it changes shape by refolding when in an acidic environment. This reconfiguration appears to allow the virus reproduce itself inside of cells.

In this study, one of the newly designed proteins was shown to block a conformational change, not only in H1 influenza hemagglutinin, but also in a similar component in H5 avian influenza.

"This finding suggests that this new protein design may have virus-neutralizing effects against multiple influenza subtypes," the researchers reported.

What was unusual about the workable designs was that they had helical binding modes, roughly shaped like a spiral staircase, rather than the loop binding that naturally occurring antibodies employ.

X-ray crystallography of the proteins complex showed that the actual orientation of the bound proteins was almost identical to the way the binding mode was designed. The modified surface of the main recognition helix on the designed protein was packed into a groove on the desired region of the virus protein.

"Overall, the crystal structure is in excellent agreement with the designed interface," the researchers noted, "with no significant deviations at any of the contact points." The design and the actual formation were nearly identical.

The scientists were encouraged by this finding. Despite their limitations, the design methods, the scientists believe, capture the essential features of the desired protein-protein interaction.

In addition to Fleishman, Whitehead, Ekiert, Wilson and Baker, other scientists on the research team were Cyrille Dreyfus of The Scripps Research Institute, Jacob E. Corn, previously at the UW but now with Genentech in San Francisco, and Eva-Maria Strauch of the UW Department of Biochemistry.

Computational designs for this study were generated on resources provided by people around the world who donate their unused home computer time as part of Rosetta@Home and by the Argonne National Leadership Computing Facility.

The project was supported by a fellowship from the Human Frontier Science Program, the Jane Coffin Child's Memorial Fund, and a career development award from the National Institute of Allergy and Infectious Disease at the National Institutes of Health. Additional support came from the Defense Advanced Research Projects Agency, the NIH yeast resource center, the Defense Threat Reduction Agency, the Howard Hughes Medical Institute, the Achievement Rewards for College Scientists Foundation, the NIH Molecular Evolution Training Program and the Skaggs Institute for Chemical Biology.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Washington. The original article was written by Leila Gray.

Journal Reference:

S. J. Fleishman, T. A. Whitehead, D. C. Ekiert, C. Dreyfus, J. E. Corn, E.-M. Strauch, I. A. Wilson, D. Baker. Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin. Science, 2011; 332 (6031): 816 DOI: 10.1126/science.1202617

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Scientists design new anti-flu virus proteins using computational methods

ScienceDaily (May 14, 2011) — A research article May 12 in Science demonstrates the use of computational methods to design new antiviral proteins not found in nature, but capable of targeting specific surfaces of flu virus molecules.

One goal of such protein design would be to block molecular mechanisms involved in cell invasion and virus reproduction.

Computationally designed, surface targeting, antiviral proteins might also have diagnostic and therapeutic potential in identifying and fighting viral infections.

The lead authors of the study are Sarel J. Fleishman and Timothy Whitehead of the University of Washington (UW) Department of Biochemistry, and Damian C. Ekiert from the Department of Molecular Biology and the Skaggs Institute for Chemical Biology at The Scripps Research Institute. The senior authors are Ian Wilson from Scripps and David Baker from the UW and the Howard Hughes Medical Institute.

The researchers note that additional studies are required to see if such designed proteins can help in diagnosing, preventing or treating viral illness. What the study does suggest is the feasibility of using computer design to create new proteins with antiviral properties.

"Influenza presents a serious public health challenge," the researchers noted, "and new therapies are needed to combat viruses that are resistant to existing anti-viral medications or that escape the body's defense systems."

They focused their attention on the section of the flu virus known as the hemagglutinin stem region. They concentrated on trying to disable this part because of its function in invading the cells of the human respiratory tract.

Their approach was somewhat similar to engineering a small space shuttle with the right configuration and construction, as well as recognizance and interlocking mechanisms, to dock with a troublesome space station and upset its mission. Only these scientists attempted their engineering feat at an atomic and molecular level.

Central to their approach is the ability of biological molecules to recognize certain other molecules or their working parts, and to have an affinity for binding to them at pre-determined locations. This recognition has both physical and chemical bases. Protein-protein interactions underlie many biological activities, including those that disarm and deactivate viruses.

In their report, the researchers described their general computational methods for designing new, tiny protein molecules that could bind to a certain spot on large protein molecules. They took apart some protein structures and watched how these disembodied sections interacted with a target surface. They analyzed particular high-affinity interactions, and used this information to further refine computer-generated designs for interfaces.

"Protein surfaces are never flat, but have many crevices and bulges at the atomic scale," lead author Sarel Fleishman explained. "The challenge is to identify amino acid side chains that would fit perfectly into these surfaces. The fit must be precise both in shape and in other chemical properties such as electrostatic charge. This geometrical and biophysical problem can be computationally solved, but requires large computational resources."

The researchers made use of a peer-to-peer computing platform called Rosetta@Home for going through the hundreds of millions of possible interactions of designed proteins and the surface of hemagglutinin to solve this challenge.

Following optimization, the designed proteins bound hemagglutinin very tightly.

Through this method, the researchers created two designs for new proteins that could bind to a surface patch on the stem of the influenza hemagglutinin from the 1918 H1N1 pandemic flu virus.

The shortcomings of the approach, due to approximations, meant that the researchers started out with 73 possibilities of which just two were successful.

One of the disease-causing characteristics of the influenza hemagglutinin stem is that it changes shape by refolding when in an acidic environment. This reconfiguration appears to allow the virus reproduce itself inside of cells.

In this study, one of the newly designed proteins was shown to block a conformational change, not only in H1 influenza hemagglutinin, but also in a similar component in H5 avian influenza.

"This finding suggests that this new protein design may have virus-neutralizing effects against multiple influenza subtypes," the researchers reported.

What was unusual about the workable designs was that they had helical binding modes, roughly shaped like a spiral staircase, rather than the loop binding that naturally occurring antibodies employ.

X-ray crystallography of the proteins complex showed that the actual orientation of the bound proteins was almost identical to the way the binding mode was designed. The modified surface of the main recognition helix on the designed protein was packed into a groove on the desired region of the virus protein.

"Overall, the crystal structure is in excellent agreement with the designed interface," the researchers noted, "with no significant deviations at any of the contact points." The design and the actual formation were nearly identical.

The scientists were encouraged by this finding. Despite their limitations, the design methods, the scientists believe, capture the essential features of the desired protein-protein interaction.

In addition to Fleishman, Whitehead, Ekiert, Wilson and Baker, other scientists on the research team were Cyrille Dreyfus of The Scripps Research Institute, Jacob E. Corn, previously at the UW but now with Genentech in San Francisco, and Eva-Maria Strauch of the UW Department of Biochemistry.

Computational designs for this study were generated on resources provided by people around the world who donate their unused home computer time as part of Rosetta@Home and by the Argonne National Leadership Computing Facility.

The project was supported by a fellowship from the Human Frontier Science Program, the Jane Coffin Child's Memorial Fund, and a career development award from the National Institute of Allergy and Infectious Disease at the National Institutes of Health. Additional support came from the Defense Advanced Research Projects Agency, the NIH yeast resource center, the Defense Threat Reduction Agency, the Howard Hughes Medical Institute, the Achievement Rewards for College Scientists Foundation, the NIH Molecular Evolution Training Program and the Skaggs Institute for Chemical Biology.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Washington. The original article was written by Leila Gray.

Journal Reference:

S. J. Fleishman, T. A. Whitehead, D. C. Ekiert, C. Dreyfus, J. E. Corn, E.-M. Strauch, I. A. Wilson, D. Baker. Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin. Science, 2011; 332 (6031): 816 DOI: 10.1126/science.1202617

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Solar power goes viral: Researchers use virus to improve solar-cell efficiency

ScienceDaily (Apr. 25, 2011) — Researchers at MIT have found a way to make significant improvements to the power-conversion efficiency of solar cells by enlisting the services of tiny viruses to perform detailed assembly work at the microscopic level.

In a solar cell, sunlight hits a light-harvesting material, causing it to release electrons that can be harnessed to produce an electric current. The new MIT research, published online in the journal Nature Nanotechnology, is based on findings that carbon nanotubes -- microscopic, hollow cylinders of pure carbon -- can enhance the efficiency of electron collection from a solar cell's surface.

Previous attempts to use the nanotubes, however, had been thwarted by two problems. First, the making of carbon nanotubes generally produces a mix of two types, some of which act as semiconductors (sometimes allowing an electric current to flow, sometimes not) or metals (which act like wires, allowing current to flow easily). The new research, for the first time, showed that the effects of these two types tend to be different, because the semiconducting nanotubes can enhance the performance of solar cells, but the metallic ones have the opposite effect. Second, nanotubes tend to clump together, which reduces their effectiveness.

And that's where viruses come to the rescue. Graduate students Xiangnan Dang and Hyunjung Yi -- working with Angela Belcher, the W. M. Keck Professor of Energy, and several other researchers -- found that a genetically engineered version of a virus called M13, which normally infects bacteria, can be used to control the arrangement of the nanotubes on a surface, keeping the tubes separate so they can't short out the circuits, and keeping the tubes apart so they don't clump.

The system the researchers tested used a type of solar cell known as dye-sensitized solar cells, a lightweight and inexpensive type where the active layer is composed of titanium dioxide, rather than the silicon used in conventional solar cells. But the same technique could be applied to other types as well, including quantum-dot and organic solar cells, the researchers say. In their tests, adding the virus-built structures enhanced the power conversion efficiency to 10.6 percent from 8 percent -- almost a one-third improvement.

This dramatic improvement takes place even though the viruses and the nanotubes make up only 0.1 percent by weight of the finished cell. "A little biology goes a long way," Belcher says. With further work, the researchers think they can ramp up the efficiency even further.

The viruses are used to help improve one particular step in the process of converting sunlight to electricity. In a solar cell, the first step is for the energy of the light to knock electrons loose from the solar-cell material (usually silicon); then, those electrons need to be funneled toward a collector, from which they can form a current that flows to charge a battery or power a device. After that, they return to the original material, where the cycle can start again. The new system is intended to enhance the efficiency of the second step, helping the electrons find their way: Adding the carbon nanotubes to the cell "provides a more direct path to the current collector," Belcher says.

The viruses actually perform two different functions in this process. First, they possess short proteins called peptides that can bind tightly to the carbon nanotubes, holding them in place and keeping them separated from each other. Each virus can hold five to 10 nanotubes, each of which is held firmly in place by about 300 of the virus's peptide molecules. In addition, the virus was engineered to produce a coating of titanium dioxide (TiO2), a key ingredient for dye-sensitized solar cells, over each of the nanotubes, putting the titanium dioxide in close proximity to the wire-like nanotubes that carry the electrons.

The two functions are carried out in succession by the same virus, whose activity is "switched" from one function to the next by changing the acidity of its environment. This switching feature is an important new capability that has been demonstrated for the first time in this research, Belcher says.

In addition, the viruses make the nanotubes soluble in water, which makes it possible to incorporate the nanotubes into the solar cell using a water-based process that works at room temperature.

Prashant Kamat, a professor of chemistry and biochemistry at Notre Dame University who has done extensive work on dye-sensitized solar cells, says that while others have attempted to use carbon nanotubes to improve solar cell efficiency, "the improvements observed in earlier studies were marginal," while the improvements by the MIT team using the virus assembly method are "impressive."

"It is likely that the virus template assembly has enabled the researchers to establish a better contact between the TiO2 nanoparticles and carbon nanotubes. Such close contact with TiO2 nanoparticles is essential to drive away the photo-generated electrons quickly and transport it efficiently to the collecting electrode surface."

Kamat thinks the process could well lead to a viable commercial product: "Dye-sensitized solar cells have already been commercialized in Japan, Korea and Taiwan," he says. If the addition of carbon nanotubes via the virus process can improve their efficiency, "the industry is likely to adopt such processes."

Belcher and her colleagues have previously used differently engineered versions of the same virus to enhance the performance of batteries and other devices, but the method used to enhance solar cell performance is quite different, she says.

Because the process would just add one simple step to a standard solar-cell manufacturing process, it should be quite easy to adapt existing production facilities and thus should be possible to implement relatively rapidly, Belcher says.

The research team also included Paula Hammond, the Bayer Professor of Chemical Engineering; Michael Strano, the Charles (1951) and Hilda Roddey Career Development Associate Professor of Chemical Engineering; and four other graduate students and postdoctoral researchers. The work was funded by the Italian company Eni, through the MIT Energy Initiative's Solar Futures Program.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Massachusetts Institute of Technology. The original article was written by David Chandler, MIT News Office.

Journal Reference:

Xiangnan Dang, Hyunjung Yi, Moon-Ho Ham, Jifa Qi, Dong Soo Yun, Rebecca Ladewski, Michael S. Strano, Paula T. Hammond, Angela M. Belcher. Virus-templated self-assembled single-walled carbon nanotubes for highly efficient electron collection in photovoltaic devices. Nature Nanotechnology, 2011; DOI: 10.1038/nnano.2011.50

Note: If no author is given, the source is cited instead.

Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

View the original article here