Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Several baffling puzzles in protein molecular structure solved with new method

02.05.2011
Determining the molecular configuration of proteins is important in nanotechology, drug design, disease research and many other fields

The structures of many protein molecules remain unsolved even after experts apply an extensive array of approaches. An international collaboration has led to a new, high-performance method that rapidly determined the structure of protein molecules in several cases where previous methods had failed.

The usefulness of the new method is reported May 1 in Nature advanced online publication. The lead authors are Dr. Frank DiMaio of the University of Washington (UW) in Seattle and Dr. Thomas C. Terwilliger of Los Alamos National Laboratory in New Mexico. The senior author is Dr. David Baker, of the UW Department of Biochemistry.

A protein's molecular structure shapes its functions. In biomedical and health research, for example, scientists are interested in the molecular structure of specific proteins for many reasons, a few of which are:

To design drugs that selectively target, at the molecular level, particular biochemical reactions in the body

To understand abnormal human proteins in disease, such as those found in cancer and neurodegenerative disorders like Alzheimer's, and how these abnormal proteins cause malfunctions

To learn the shape and function of virus particles and how they act to cause infections

To see how the chains of amino acids, decoded from the DNA in genes, fold and twist into normally or abnormally shaped protein molecules

To design new proteins not found in the natural world, such as enzymes to speed up a slow biochemical reaction

To find ways to replace malfunctioning molecular parts of proteins that are critical to health

To devise nano-scale tools, such as molecular motors

"The important new method described this week in Nature highlights the value of computational modeling in helping scientists to determine the structures and functions of molecules that are difficult to study using current techniques," said Dr. Peter Preusch, who oversees Baker's research grant and other structural biology grants at the National Institutes of Health (NIH). "Expanding the repertoire of known protein structures -- a key goal of the NIH Protein Structure Initiative, which helped fund the research – will be of great benefit to scientists striving to design new therapeutic agents to treat disease."

The methods devised by the group overcome some of the limitations of X-ray crystallography in determining the molecular structure of a protein. X-ray crystallography obtains information about the positions of atoms, chemical bonds, the density of electrons and other arrangements within a protein molecule.

The information is gleaned by striking protein crystals with X-ray beams. The beams bounce off in several directions.

Measuring the angles and intensities of these diffracted beams enables scientists to produce a 3-dimensional image of electron density. However, information about the molecular structure can be lost in taking the measurements, due to restraints posed by physics.

Scientists attempt to sidestep this problem by comparing the crystallography results to previously solved protein structures that resemble the unknown structure. The technique to "fill in the blanks" is called molecular replacement.

Molecular replacement has its own limitations in interpreting the electron density maps produced by X-ray crystallography, according to the authors of the paper. Techniques such as automatic chain tracing often follow the comparative model more closely than the actual structure of the protein under question. These mistakes lead to failure to obtain an accurate configuration of the molecule.

The researchers showed that this limitation can be substantially reduced by combining computer algorithms for protein structure modeling with those for determining structure via X-ray crystallography.

Several years ago, University of Washington researchers and their colleagues developed a structure prediction method called Rosetta. This program takes a chain of amino acids – protein-building blocks strung all in a row -- and searches for the lowest energy conformation possible from folding, twisting and packing the chain into a three-dimensional (3-D) molecule.

The researchers found that even very poor electron density maps from molecular replacement solutions could be useful. These maps could guide Rosetta structural prediction searches that are based on energy optimization. By taking these energy-optimized predicted models, and looking for consistency with the electron density data contained in the X-ray crystallography, new maps are generated. The new maps are then subjected to automatic chain tracing to produce 3-D models of the protein molecular structure. The models are checked with a sophisticated monitoring technique to see if any are successful.

To test the performance of their new integrated method, the researchers looked at 13 sets of X-ray crystallography data on molecules whose structures could not be solved by expert crystallographers. These structures remained unsolved even after the application of an extensive array of other approaches. The new integrated method was able to yield high resolution structures for 8 of these 13 highly challenging models.

"The results show that structural prediction methods such as Rosetta can be even more powerful when combined with X-ray crystallography data," the researchers noted. They added that the integrated approach probably outperforms others because it provides physical chemistry and protein structural information that can guide the massive sampling of candidate configurations. This information eliminates most conformations that are not physically possible.

Our procedures, the authors noted, required considerable computation, as up to several thousand Rosetta model predictions are generated for each structure. The researchers have developed automated procedures that potentially could narrow down the possibilities and lessen the number of times a model is rebuilt to make corrections. This automation could reduce computing time.

Through Baker's laboratory, many members of the general public contribute their unused home computer time to help in the effort to obtain structural models of proteins that are biologically and medically significant. The scientific discovery game is called "Fold It." (http://fold.it/portal/)

Other authors of the paper appearing this week in Nature are Dr. Randy J. Read of the University of Cambridge, United Kingdom; Dr. Alexander Wlodawer of the National Cancer Institute; Drs. Gustav Oberdorfer and Ulrike Wagner of University of Graz, Austria; Dr. Eugene Valkov of the University of Cambridge; Drs. Assaf Alon and Deborah Fass of the Weizmann Institute of Science in Rehovot, Israel; Drs. Herbert L. Axelrod and Debanu Das of the SLAC National Accelerator Laboratory in Menlo Park, Calif.; Dr. Sergey M. Vorobiev of Columbia University in New York; and Dr. Hideo Iwai of the University of Helsinki, Finland.

The research was funded by the National Institute of General Medical Sciences and the National Center for Research Resources at the National Institutes of Health, the Howard Hughes Medical Institute, the Israel Science Foundation, DK Molecular Enzymology, Austrian Science Fund, the Center for Cancer Research at the National Cancer Institute, the Academy of Finland, and the U.S. Department of Energy's Office of Science, Biological and Environmental Research. The Joint Center for Structural Genomics, which is supported by the NIH's Protein Structure Initiative, contributed to the protein production and structural work.

Leila Gray | EurekAlert!
Further information:
http://www.washington.edu

More articles from Life Sciences:

nachricht Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>