$1.7 million for the group of Volker Dötsch/ research on pharmaceutically relevant membrane protein structures and dynamics

FRANKFURT. The research group of Prof. Volker Dötsch at the Institute for Biophysical Chemistry at Goethe University is involved in two international research grants funded by the National Institutes of Health (NIH). These interdisciplinary teams of scientists will use state-of-the-art biophysical and computational methods to understand how the structure and dynamics of membrane proteins determine their functions. Over the next 5 years the group will receive $ 344,000 per year for the two consortia („Membrane Protein Structures by Solution NMR” and “The Center for Membrane Protein Structure and Dynamics”).

Schema of the formation of plaques in the brain of patients with Alzheimers disease.

Although more than 50% of all pharmaceutical drugs function via membrane proteins, to date very little is known about the structures and processes involving membrane proteins. Therefore the NIH granted the „Membrane Protein Structural Dynamics Consortium“ coordinated by the University of Chicago. Scientists from 14 institutes of four different countries are involved. Included in this international team is the research group of Volker Dötsch at the Institute of Biophysical Chemistry. Over the last couple of years researchers in his group led by Frank Bernhard have developed a cell-free protein expression system that enables researchers to express roughly 80% of all membrane proteins – both prokaryotic and eukaryotic ones. Since membrane proteins are notoriously difficult to express in cellular systems, the cell-free expression system provides a very interesting alternative approach to obtain the large quantities of material required for detailed biochemical and biophysical investigations.

The group developed a new method for labeling membrane proteins with selectively labeled amino acids which allows them to determine the structure of membrane proteins via NMR spectroscopy, which is very difficult with conventional approaches. With this expertise they play a part in the second NIH funded project: „Membrane Protein Structures by Solution NMR“. One recent success of the Dötsch group is the determination of the C-terminal part of Presenilin 1. Presenilin is involved in the formation of precursors of plaques, which are a hallmark of the Alzheimers disease. The further development of these techniques is one aim of the this research consortium, coordinated by the Harvard Medical School. In addition to the Frankfurt group, two research groups of the Vanderbilt University and one at the Los Alamos National Laboratory, US, are involved.

This article was originally published at Genomeweb BioInform (link).

A new consortium launched with the aim of understanding the structure and dynamic function of membrane proteins will likely result in an improved informatics toolbox for modeling proteins and other biomolecules.

Last month, the National Institute of General Medical Science launched the Membrane Protein Structural Dynamics Consortium, an interdisciplinary team of researchers that aim to use biophysical and computational methods to understand the structure, function, and dynamics of membrane proteins.

The consortium, funded by a five-year $22.5 million “glue grant” from NIGMS, comprises 30 scientists from 14 institutions in four countries and is hailed as one of the largest and most comprehensive projects focused on membrane proteins to date.

Led by researchers at the University of Chicago, the consortium also includes scientists from Cornell University, Columbia University, Germany’s Johann Wolfgang Goethe-Universität, the National Institutes of Health, Stanford University, University of California-Los Angeles, University of Illinois, University of Pittsburgh, University of Toronto, University of Virginia, University of Wisconsin, the Netherlands’ Utrecht University, and Vanderbilt University.

The project is expected to help scientists better understand a wide range of ailments caused by faulty membrane proteins, such as some forms of heart disease, diabetes, and neurological and hormonal disorders. Ultimately, since more than half of drugs currently on the market target membrane proteins, the project could pave the way for developing new or improved drugs and therapies.

The project will involve a combination of structural biology, magnetic resonance, fluorescence spectroscopy, biochemistry, and biophysics techniques, and will also have a very large computational component. Rather than assign the task of computational tool development to individual labs, the consortium has opted to delegate the task to a select group of researchers, dubbed the computational core, who have considerable expertise in that arena.

Benoit Roux, a professor of biochemistry and molecular biophysics at the University of Chicago and one of the members of the core, told BioInform that the group aims to develop tools centered around four specific aims: to generate different kinds of force fields for proteins; integrate data at different scales and resolutions; identify pathways between different conformations of proteins; and interpret spectroscopic measurements, which are often “ambiguous.”

Along similar lines, Harel Weinstein, a professor of physiology and biophysics at Cornell University, said the group will develop tools for “large-scale simulations” of protein structures that realistically represent the protein and its fluid environment, as well as tools to let researchers look at protein dynamics based on known structures and to interpret “a new generation of data” from things like single molecule experiments. The team also hopes to improve on “sophisticated” tools that are currently used in computational biology labs.

“That is quite complicated and requires several levels of new thinking … in terms of the use of computational resources [such as] parallelization and new types of processors,” he told BioInform. “We are trying to develop analysis tools that reduce the data to the same kinds of components [that] everybody [can] understand — even those who are not using the [same] experimental tool[s] for data acquisition.”

Roux said that the developers plan to use existing tools that they have developed in their labs, which they will “extend” to work in a more “general fashion.”

“It’s a challenge because [the proteins are] a bit more disparate … you have a channel, a pump, you have maybe a receptor … being analyzed,” he said. “The tool has to be general enough that it’s suitable for all these problems but not so general that it becomes a bit abstract.”

An additional challenge for the core, Weinstein said, will be to develop tools that can be easily used by experimental biologists involved in the consortium who don’t have intensive bioinformatics training. On that score, he said the consortium is considering conducting workshops that will provide training on how to use the tools.

The computational core also plans to develop a centralized database to store and integrate project data in a format that consortium members can make sense of no matter what tool was used to collect the experimental data, Weinstein said.

The planned database will be different from repositories like the Protein Structure Initiative’s Structural Biology Knowledgebase in the sense that “the same people who create the tools for dissemination and disseminate the data are the people who collect the data” he said.

“I could put my data in [PSI]; it’s a very useful tool,” Weinstein acquiesced. “What is different is [the consortium's database] is created for people who work together and who refine the database all the time as they work.”

The PSI knowledgebase is a product of the Protein Structure Initiative launched by NIGMS in 1999 with the long-term goal of making it easy to obtain three-dimensional atomic-level structures of proteins by looking at their DNA sequences.

Filling the Gap

Computational core member Ivet Bahar, a professor of computational biology at the University of Pittsburgh, told BioInform that her team plans to use “elastic network models” to analyze membrane proteins without compromising the resolution.

She said that although her models, developed over a decade ago, have been used to study other molecules, reworking these tools to work for membrane proteins is a greater challenge because they have to take into account the membrane as well as how the protein interacts with the membrane, among other things.

Membrane proteins, along with the lipid and water molecules that surround and interact with them, create large complex systems that are difficult to model, explained Bahar.

“My lab simplifies the analysis of such complex systems by using simplified models … [that] help us understand the mechanisms [and] the machinery of [the] biological processes,” she said.

According to Bahar, the models her team develops “approximate” proteins and other biomolecules as “elastic materials” such as beads and elastic springs, which provides insights into which structures are the most “energetically favorable” for different functions.

Read more at Genomeweb Bioinform »

This article was originally published at the UChicago Medical Center Science Life blog (link).

The structure of the agitoxin-Shaker channel complex (from Benoit Roux’s lab webpage)

Scientific grants are usually given out one investigator at a time, funding a single laboratory’s research. But as the questions of science grow larger, and the technology needed to answer those questions grows ever more specialized and expensive, funding collaborative grants becomes increasingly common practice. One type of multi-investigator grant has been dubbed a “glue” grant, so named because it sticks together researchers from several different institutions for the common pursuit of one important science goal.

Today, the National Institute of General Medical Sciences announced a glue grant on the topic of membrane proteins, an effort that will be led from right here on the University of Chicago campus. The grant formally creates the Membrane Protein Structural Dynamics Consortium, a team of nearly 30 scientists from 14 institutions in the United States, Germany, Canada, and the Netherlands.

“We have been able to put together almost a dream team of people currently involved in this type of research,” said Eduardo Perozo, PhD, Professor of Biochemistry and Molecular Biophysics at the University of Chicago Medical Center and the leader of the team. “There has been nothing like this project before.”

Membrane proteins are the machines on the factory floor of the cell’s surface, tasked with letting materials in and out of the cell, responding to signals from other cells, and even producing energy. The family includes ion channels that Perozo (and fellow team member Benoit Roux) study, the receptors for neurotransmitters and hormones, and various other pumps, transporters, and exchangers. Figuring out how these miniature machines function will be extremely helpful in designing new drugs, both to treat diseases caused by defective membrane proteins and for improving drugs that rely upon membrane proteins to get to their target.

Traditionally, the study of membrane proteins is bifurcated into those who research their structure and those who research their function. The new glue grant-funded effort will concentrate on the connections between those two fields of study, Perozo said, uniting the best scientists to study membrane protein dynamics.

To do so, the grant will establish communal core facilities at various institutions involved in the consortium, each with their own specialty. For example, one laboratory may create a library of new antibodies useful for experiments, while another laboratory might specialize in imaging techniques such as magnetic resonance or fluorescence spectroscopy, and another offers advanced computation for complex modeling. All of the researchers involved in the effort can then utilize the facilities for their own experiments, with access eventually expanding to the scientific community at large.

“We intend to start with targets for which we know the static structure at high resolutions and the function on a certain level, but don’t know how they connect through dynamics,” Perozo said. “Eventually, we want to develop a set of tools and reagents to be able to engineer or alter normal activity in these systems.”

This article was originally published at UChicago News (link).

The outer surface of cells is a factory floor of machines with varied functions: exchanging materials in and out, receiving signals, and generating energy. Studying these machines, called membrane proteins, is one of the greatest challenges of science, crucial for understanding cellular biology and developing new drugs to fight disease.

One of the largest and most comprehensive collaborations to understand the structure and dynamic function of membrane proteins was officially launched Aug. 10 with a five-year, $22.5 million grant from the National Institute of General Medical Sciences. The funding, known as a “glue grant,” unites nearly 30 scientists from 14 institutions in four different countries into an effort called the Membrane Protein Structural Dynamics Consortium.

“We have been able to put together almost a dream team of people currently involved in this type of research,” said Eduardo Perozo, Professor of Biochemistry and Molecular Biology at the University of Chicago Medical Center and the leader of the team. “There has been nothing like this project before.”

Research on membrane proteins has traditionally been divided into two groups: structure and function. The new collaboration will focus on uniting those two areas through the study of dynamics, how a membrane protein changes shape and function over time.

To do so, the effort will unite experts across disciplines and knowledgeable in a wide range of cutting-edge technologies, including magnetic resonance and fluorescence spectroscopy, computational modeling and electrophysiology. Core facilities for different techniques will be set up at institutions for shared use by all members of the consortium – and eventually the scientific community at large.

Deeper knowledge of membrane protein dynamics will enable the development of better drugs for diseases involving defective channels and transporters, such as forms of heart disease, diabetes, and neurological and hormonal disorders. Understanding how membrane proteins allow molecules into and out of cells also can help improve drug design and delivery for an even wider range of diseases.

“We intend to start with targets for which we know the static structure at high resolutions and the function on a certain level, but don’t know how they connect through dynamics,” Perozo said. “Eventually, we want to develop a set of tools and reagents to be able to engineer or alter normal activity in these systems.”

The Membrane Protein Structural Dynamics Consortium includes scientists at Cornell University, Columbia University, Johann Wolfgang Goethe-University at (Germany), the National Institutes of Health, Stanford University, the University of California-Los Angeles, the University of Chicago, the University of Illinois, the University of Pittsburgh, the University of Toronto (Canada), the University of Virginia, the University of Wisconsin, Utrecht University (the Netherlands) and Vanderbilt University.