Ensuring Synchrotron Beamline Access for Biomedical Researchers

The National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory (BNL) closed earlier this week as a newer, more advanced facility, NSLS-II Exit icon, began to come online.

Thousands of NIH researchers have used beamlines at NSLS over the last 30 years to collect data to characterize biological macromolecules including drug targets, ion pumps and enzymes. Because the beamlines for biological research Exit icon at NSLS-II will not be available until 2016, other synchrotron facilities are temporarily expanding their capacity to address the beamline reduction.

Here are some sources that will help you identify and access beamlines at other U.S. synchrotrons:

If you have questions about NIH-funded synchrotron resources, please contact me or Ward Smith.

Protein Data Bank Passes 100,000-Structure Mark

Protein Data Bank (PDB) counter showing 100,147 total number of entries.
The latest update brings the total number of PDB entries to 100,147.

The Protein Data Bank (PDB) Exit icon just passed a major threshold—the release of its 100,000th entry. This free online repository of experimentally determined protein and nucleic acid structures, which NIGMS and other parts of NIH have helped fund since 1978, facilitates atomic-level insight into protein structure and function. PDB is widely used by the scientific community to study basic biological processes like transcription, translation, enzymology, bioenergetics and metabolism and also for more medically oriented investigations into disease mechanisms and drug design.

In addition to scientists, students and educators use the digital resource for their own explorations of protein structure, function and interactions as well as to gain greater knowledge about biology.

Number of structures available in the PDB per year, with selected examples. For details, see http://www.eurekalert.org/multimedia/pub/73206.php?from=267554 Exit icon.

Approximately 260,000 visitors access PDB each month. Scientists around the world currently deposit about 200 structures per week, which PDB staff review, annotate and augment with links to other relevant biological data. To meet the challenges posed by large structures, complex chemistry and use of multiple experimental methods, the repository recently launched a software tool for structure deposition and annotation Exit icon.

If you aren’t already a PDB user, I encourage you to check out its resources to see if they could help advance your research.

 

Give Input on Structural Biology Resource and Infrastructure Needs

Earlier this year, I told you about the formation of two committees focused on Protein Structure Initiative (PSI) transition planning. These committees are charged with determining what unique resources and capabilities developed during the PSI should be preserved after the initiative ends and how this preservation should be done.

An important part of this process is getting input from the community, so we have just issued a request for information (RFI), NOT-GM-14-115, seeking comments about structural biology resources that have a high impact on the community, whether those resources have been supported through the PSI or by other means. We also want to hear what you think about the future of structural biology-related technology development, which has been an important feature of the PSI.

While the RFI invites comments on these specific topics, you should not feel limited to them—we welcome any comments that you feel are relevant.

To respond to the RFI, send an e-mail to nigmspsirfi@mail.nih.gov by May 23, 2014. When we compile the responses, we’ll remove any personal identifiers like names and e-mail addresses and only use de-identified comments.

If you have any questions about the RFI or the transition committees, please let me know.

International Year of Crystallography Is Under Way

A crystal of hen egg white lysozyme. Credit: Alex McPherson, University of California, Irvine.
A crystal of hen egg white lysozyme. Credit: Alex McPherson, University of California, Irvine.

As you may know from the coverage in various popular news outlets and science journals (see below for a list), the United Nations Educational, Scientific and Cultural Organization has declared 2014 to be the “International Year of Crystallography Exit icon.” This is in recognition of the 100th anniversary of the Nobel Prize in physics to Max von Laue for the discovery of diffraction of X-rays by crystals.

I first learned about crystallography in college, when I took a course in physical chemistry that included an introduction to chemical crystallography. Crystallography combines math, computer science, chemistry and biology—and that’s what convinced me to do graduate work in the field. When you determine structures, you’re often the first person to ever see that molecule, and that’s pretty exciting.

Since 1914, scientists have made many advances in the use of X-rays for the atomic-level determination of the 3-D structure of molecules. For instance, in the early years of the 20th century, William and Lawrence Bragg, father and son, learned that the newly discovered X-ray radiation could be used to locate the atoms in a crystal of matter. Their work ultimately led to Bragg’s Law for understanding X-ray diffraction and the structure determination of materials ranging from table salt to the ribosome. Breakthroughs made possible by crystallography (and diffraction) have led to 15 Nobel Prizes, including 7 with NIGMS support.

X-ray crystallography has impacted all areas of science, including biomedical research. The first biological finding was made by James Sumner, who discovered that enzymes could be crystallized (urease was the enzyme). In the years following, X-ray diffraction and crystallography have been used to reveal the structure of DNA and countless proteins and enabled structure-based drug design efforts. Crystallography has become an established tool of small molecule and protein studies.

Today, modern biological crystallography is practiced at synchrotron facilities, with access to 20 X-ray crystallography beamlines supported entirely or in part by NIGMS. Efforts are under way to make smaller, more intense beamlines that will allow the study of small crystals. Crystallography is also very much a part of the new X-ray laser facilities, where several NIGMS investigators are carrying out pioneering research on very small crystals of proteins, including membrane proteins, on X-ray scattering of proteins in solution and on protein dynamics.

Clearly, crystallography continues to be a cutting-edge field, and I’m excited to see what advances it brings during the coming years.

Articles about the International Year of Crystallography:

January 30 Special Issue of Nature Exit icon
UN to Raise Awareness of Little-Known Science Behind DNA, Computer Memory, New Drugs Exit icon
2014 Is the International Year of Crystallography (‘What’s Crystallography?’ You Ask) Exit icon

Protein Structure Initiative Transition Planning Committees

Shortly after NIGMS Director Jon Lorsch announced plans to sunset the Protein Structure Initiative after the completion of the PSI:Biology phase in 2015, he commissioned two committees to determine what unique resources and capabilities developed during the PSI should be preserved and how that should be done. The committees, which are working together, held their first meetings in December and expect to present their recommendations within the year.

The external committee, which includes practitioners of structural biology and biomedical researchers who use structural biology data and resources in their work, will primarily focus on community needs. It also will suggest emerging challenges and opportunities in structural biology.

The internal committee, which is composed of NIH staff, will focus on how to implement the priorities identified by the external committee. The group includes a member from each NIGMS scientific division as well as several representatives from other NIH institutes who have experience managing structural biology and large, complex research programs.

The work of these committees will help define how we can provide continued access to important structural biology resources and identify new directions for technology development with potential for broad biomedical impact.

As Jon wrote in a Feedback Loop post about bolstering support for investigator-initiated research and as also reported in a Nature news article Exit icon, the decision to sunset a large set-aside program that has received substantial investments, such as the PSI, should not be interpreted as a lack of support for team science. Multidisciplinary collaborations are likely to become increasingly important as we delve deeper into complex biological problems, and we will continue to sponsor team approaches to biomedical research. We also remain committed to supporting structural biology research through investigator-initiated grant mechanisms, innovative technology development and access to critical resources.

Examining Our Large-Scale Research Initiatives and Centers, Including the PSI

There have been a lot of discussions lately at NIGMS about large-scale research initiatives and centers. In these conversations, we have drawn a distinction between initiatives and centers focused mainly on research and those focused mainly on resources. Examples of the latter include our human cell repository, synchrotron light sources, and databases, all of which serve the biomedical community in critical ways and, in most cases, require sustained support. In contrast, many of us feel that the primary purpose of research-focused initiatives and centers is to open untapped scientific areas, providing an initial, targeted investment that enables the research to develop sufficiently so that it can be sustained through other grant mechanisms, such as R01s and P01s.

Our discussions have led to the question of whether, when and how research initiatives and centers should be ended. Should all new research initiatives and centers have hard “sunset clauses” built into them, for example at 10 years, similar to what is done for projects funded by the NIH Common Fund? Or should it be possible for them to continue indefinitely as long as they are sufficiently productive?

An additional consideration is that many of our currently funded initiatives and centers were developed during the period in which the NIH budget was doubling (see figure). With a large infusion of new investment into biomedical research, it made sense to use a significant portion of the funds to open up new scientific territory through large-scale exploration in ways that were not previously possible.

Center Funding as a Proportion of the NIGMS Budget
Fiscal Years 1998-2012
Growth of NIGMS funding for centers (blue bars, left axis) for Fiscal Years 1998-2012. The total NIGMS budget each year during the same period is also shown (red line, right axis). The numbers on top of each blue bar represent the percentage of the total NIGMS budget committed to centers in that year. The data for 2012 do not include the funds for the Institutional Development Award (IDeA) program or the Biomedical Technology Research Centers program, which were transferred to NIGMS from the former National Center for Research Resources in that fiscal year.
View larger image
Growth of NIGMS funding for centers (blue bars, left axis) for Fiscal Years 1998-2012. The total NIGMS budget each year during the same period is also shown (red line, right axis). The numbers on top of each blue bar represent the percentage of the total NIGMS budget committed to centers in that year. The data for 2012 do not include the funds for the Institutional Development Award (IDeA) program or the Biomedical Technology Research Centers program, which were transferred to NIGMS from the former National Center for Research Resources in that fiscal year.

In the current budget environment, in order to start a new program or bolster support for existing priorities such as investigator-initiated research, other programs must be adjusted or ended.

These issues will be central as we begin a strategic planning process to ensure that we are using the most effective and efficient mechanisms to invest the taxpayers’ money in fundamental biomedical and behavioral research. We have already begun carefully examining our existing portfolio of research initiatives and centers and considering how to balance continued support for them with other priorities and opportunities.

At last week’s National Advisory General Medical Sciences Council meeting, Council members and staff discussed the future of one existing large-scale program, the Protein Structure Initiative (PSI). The Council heard the results of a midpoint evaluation of the PSI’s third 5-year phase, PSI:Biology. The evaluators found that PSI investigators have determined an impressive number of high-quality protein structures and that some of the program’s accomplishments, including methodological ones, could not have been readily achieved through R01-type investigator-initiated grants.

The evaluators concluded that the PSI will reach a point that no longer justifies set-aside funding and, as a result, strongly recommended that NIGMS begin planning the sunset of the PSI, being careful to identify resources developed by the initiative that should be retained for use by the biomedical community.

After numerous internal discussions and consultation with the Council, we have decided to follow this advice and begin planning to sunset the PSI in its current format after the completion of PSI:Biology in 2015. We are setting up two transition-planning committees, one made up of NIGMS staff and representatives from several other parts of NIH, and a second made up of scientists from the research community. These committees will work together to recommend the best methods for phasing out the program and identifying critical resources that should be retained. The committees will also suggest emerging challenges and opportunities in structural biology that may require new, smaller-scale targeted support.

The committees and NIGMS will need a great deal of input from the biomedical community as this transition-planning process moves forward. I hope that you will freely share your thoughts and suggestions with us, now and in the future.

Improving Homology Modeling

While the Protein Data Bank includes nearly 88,000 protein structures that were determined experimentally, there are millions more proteins whose structures are unknown. Comparative or homology modeling offers a powerful approach for leveraging solved structures to reveal important biological details about the others.

Two efforts, both funded through the Protein Structure Initiative, are evaluating the current state of our ability to model protein structures and complexes and seeking ways to further advance the accuracy and usefulness of homology modeling.

GPCR Dock 2013

The NIGMS-funded GPCR Network Exit icon is hosting its third round of the GPCR Docking and Modeling Assessment, GPCR Dock 2013. This assessment of homology modeling and docking methods is focused specifically on G protein-coupled receptors (GPCRs), seven-transmembrane proteins that help transmit essential signals from a wide range of hormones and neurotransmitters in the body and that are a major target of existing drugs. Participants will submit prediction models for four target GPCR-ligand complexes recently determined by GPCR Network investigators and yet to be published. An analysis of the results will be available a few months after the March 3 submission deadline. To participate, register by February 1 Exit icon. For more information, contact the organizers.

Technology Development for Protein Modeling Funding Opportunity

As I stated last month, we have reissued the Technology Development for Protein Modeling (R01) funding opportunity announcement. It encourages grant applications from institutions that propose to develop novel technologies that will significantly improve the accuracy of comparative modeling methods for protein structure prediction. Applicants should focus on one or both of these goals:

  • Near-crystal-structure quality for close homologs of known structures, and/or
  • High-accuracy models for remote homologs of known structures.

Crystallography Gets Support from United Nations, NIGMS

Laue X-ray diffraction pattern of a single crystal of a dimeric hemoglobin taken at the BioCARS structural biology research center. Credit: Vukica Srajer, BioCARS/University of Chicago, and William Royer, Jr., University of Massachusetts Medical School
Laue X-ray diffraction pattern of a single crystal of a dimeric hemoglobin taken at the BioCARS structural biology research center. Credit: Vukica Srajer, BioCARS/University of Chicago, and William Royer, Jr., University of Massachusetts Medical School

As NIH Director Francis Collins recently noted on his blog, this year marks the 100th anniversary of the first experiment demonstrating that X-rays are diffracted by crystals. Two years later, this discovery was recognized with a Nobel Prize in physics. For this and other reasons, the United Nations has designated 2014 as the International Year of Crystallography Exit icon. The designation offers an opportunity for organizations worldwide to increase public awareness of the field and promote access to crystallographic knowledge and activities.

X-ray crystallography is central to many areas of basic biomedical research, and NIGMS supports a number of major crystallographic efforts that may be of interest and use to you.

Since 2000, our Protein Structure Initiative (PSI) has undertaken the high-throughput determination of protein structures by crystallography and NMR methods, resulting in the deposition in the public Protein Data Bank Exit icon of more than 5,000 macromolecular structures. The initiative’s current phase focuses on the determination of biologically relevant and important structures. Members of the scientific community can nominate proteins Exit icon for structure determination, order protein plasmids and empty vectors Exit icon, and access PSI data and other resources Exit icon. Active PSI funding opportunities solicit applications for Technology Development for High-Throughput Structural Biology Research (R01) and Technology Development for Protein Modeling (R01).

We also have been involved in supporting the construction, upgrade and maintenance of synchrotron beamline stations for X-ray crystallographic studies. These activities include a state-of-the-art facility Exit icon at the Advanced Photon Source at Argonne National Laboratory, which we established in partnership with the National Cancer Institute. Our support of synchrotron facilities and of crystallographic technology development has improved access for NIH grantees and other users and increased the capacity for crystallographic data collection.

In addition, we now oversee the Biomedical Technology Research Centers, several of which focus on developing and applying innovative crystallography techniques. These resource centers provide broad access to instruments, methods, software, expertise and hands-on training.

I look forward to sharing more details about the International Year of Crystallography as activities get under way.

Invitation to Structure Determination Technologies Workshop

Protein structureWe welcome structural biologists and biologists engaged in functional investigations that benefit from structural data to participate in our PSI:Biology Technologies Workshop at NIH on December 12, 2012.

The workshop will focus on new technologies for high-throughput protein structure determination developed within our Protein Structure Initiative, which is now in a phase called PSI:Biology. Investigators from the initiative will present their latest data and highlight problems and solutions specifically related to protein-protein, protein-ligand, protein-nucleic acid and other macromolecular complexes. In addition to exchanging ideas, workshop participants will have the opportunity to meet potential collaborators.

This meeting is the latest in a series of popular and very productive annual events, dubbed “bottlenecks” and “enabling technologies” workshops. Registration, which is now open, is free. If you have questions, especially as we build the agenda, or require any other assistance, please e-mail me or Alexandra Ainsztein or call us at 301-594-4428 or 301-594-0828, respectively.

Expression Plasmids and Empty Vectors Available

PSI:Biology-Materials Repository bannerGreat news for biochemists, biologists and structural biologists—more than 50,000 protein expression plasmids and almost 100 empty vectors are now available through the PSI:Biology-Materials Repository Exit icon. This includes about 900 membrane protein plasmids, and we expect this number—plus that for human proteins—to grow in the coming months.

The repository has carefully collected, maintained and annotated these materials generated by scientists involved in the Protein Structure Initiative. In addition, it has developed and optimized the empty vectors for producing proteins in bacteria, yeast and cell-free systems. For a modest charge, you can order the plasmids and vectors from the online catalog Exit icon.

Many of the plasmids represent proteins whose crystal structures have been determined but whose biological functions are not yet known. Search the repository Exit icon or use the Functional Sleuth Exit icon to find out if the structure of your favorite protein or a similar one has already been determined.

If you can’t locate the plasmids you need in the PSI collection, you might search the larger DNASU plasmid repository Exit icon, which houses the PSI:Biology Materials Repository. This central repository offers plasmids from hundreds of organisms and special collections, including human kinases, the Thermotoga maritime genome and a new set of 180 glycoenzymes.