Theodor Agapie Wins American Chemical Society Award

Theodor Agapie, assistant professor of chemistry at Caltech, has received the 2013 Award in Pure Chemistry from the American Chemical Society (ACS). The award will be presented at the national meeting of the ACS in New Orleans in April.

ACS is recognizing Agapie for his laboratory research on inorganic compounds. According to Agapie, his lab is working toward developing catalysts for artificial photosynthesis, a promising area of research into sustainable energy.

"I am very honored and thrilled to have received this award, particularly because I think it provides recognition for the efforts of my entire research team," says Agapie. "I have been lucky to work with a group of very talented young scientists who made the discoveries noted in this award."

Agapie, a native of Romania, received his bachelor's degree from MIT in 2001 and his PhD from Caltech in 2007. He has been an assistant professor at Caltech since early 2009. Since joining Caltech's faculty, Agapie has been named a Searle Scholar, a Sloan Research Fellow, and the recipient of a National Science Foundation CAREER Award. The Award in Pure Chemistry comes with a $5,000 prize and travel expenses for the upcoming national meeting of the American Chemical Society.

 

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Tuesday, April 9, 2013
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Spring Teaching Assistant Orientation

Caltech Modeling Feat Sheds Light on Protein Channel's Function

PASADENA, Calif.—Chemists at the California Institute of Technology (Caltech) have managed, for the first time, to simulate the biological function of a channel called the Sec translocon, which allows specific proteins to pass through membranes. The feat required bridging timescales from the realm of nanoseconds all the way up to full minutes, exceeding the scope of earlier simulation efforts by more than six orders of magnitude. The result is a detailed molecular understanding of how the translocon works.

Modeling behavior across very different timescales is a major challenge in modern simulation research. "Computer simulations often provide almost uselessly detailed information on a timescale that is way too short, from which you get a cartoon, or something that might raise as many questions as it answers," says Thomas Miller, an assistant professor of chemistry at Caltech. "We've managed to go significantly beyond that, to create a tool that can actually be compared against experiments and even push experiments—to predict things that they haven't been able to see."

The new computational model and the findings based on its results are described by Miller and graduate student Bin Zhang in the current issue of the journal Cell Reports.

The Sec translocon is a channel in cellular membranes involved in the targeting and delivery of newly made proteins. Such channels are needed because the proteins that are synthesized at ribosomes must travel to other regions of the cell or outside the cell in order to perform their functions; however, the cellular membranes prevent even the smallest of molecules, including water, from passing through them willy-nilly. In many ways, channels such as the Sec translocon serve as gatekeepers—once the Sec translocon determines that a given protein should be allowed to pass through, it opens up and allows the protein to do one of two things: to be integrated into the membrane, or to be secreted completely out of the cell.

Scientists have disagreed about how the fate of a given protein entering the translocon is determined. Based on experimental evidence, some have argued that a protein's amino-acid sequence is what matters—that is, how many of its amino acids interact favorably with water and how many clash. This argument treats the process as one in equilibrium, where the extremely slow rate at which a ribosome adds proteins to the channel can be considered infinitely slow.  Other researchers have shown that slowing down the rate of protein insertion into the channel actually changes the outcome, suggesting that kinetic effects can also play a role.

"There was this equilibrium picture, suggesting that only the protein sequence is really important. And then there was an alternative picture, suggesting that kinetic effects are critical to understanding the translocon," Miller says. "So we wondered, could both pictures, in some sense, be right? And that turns out to be the case."

In 2010 and earlier this year, Miller and Zhang published papers in the Proceedings of the National Academy of Sciences and the Journal of the American Chemical Society describing atomistic simulations of the Sec translocon. These computer simulations attempt to account for every motion of every single atom in a system—and typically require so much computing time that they can only model millionths of seconds of activity, at most. Meanwhile, actual biological processes involving proteins in the translocon last many seconds or minutes.

Miller and Zhang were able to use their atomistic simulations to determine which parts of the translocon are most important and to calculate how much energy it costs those parts to move in ways that allow proteins to pass through. In this way, they were able to build a simpler version of the simulation that modeled important groupings of atoms, rather than each individual atom. Using the simplified simulation, they could simulate the translocon's activity over the course of more than a minute.

The researchers ran that simplified model tens of thousands of times and observed the different ways in which proteins move through the channel. In the simulation, any number of variables could be changed—including the protein's amino-acid sequence, its electronic charge, the rate at which it is inserted into the translocon, the length of its tail, and more. The effect of these alterations on the protein's fate was then studied, revealing that proteins move so slowly within the tightly confined environment of the translocon that the pace at which they are added to the channel during translation—a process that might seem infinitely slow—can become important. At the same time, Miller and Zhang saw that other relatively fast processes give rise to the results associated with the equilibrium behavior.

"In fact, both equilibrium and kinetically controlled processes are happening—but in a way that was not obvious until we could actually see everything working together," Miller says.

Beyond elucidating how the translocon works and reconciling seemingly disparate experimental results, the new simulation also lets the researchers perform experiments computationally that have yet to be tried in the lab. For example, they have run simulations with longer proteins and observed that at such lengths—unlike what has been seen with shorter proteins—the equilibrium picture begins to be affected by kinetic effects.  "This could bring the two experimental camps together, and to have led that would be kind of exciting," Miller says.

The new Cell Reports paper is titled "Long-timescale dynamics and regulation of Sec-facilitated protein translocation." The work was supported by the U.S. Office of Naval Research and the Alfred P. Sloan Foundation, with computational resources provided by the U.S. Department of Energy, the National Science Foundation, and the National Institute of General Medical Sciences.

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Barton Elected to Institute of Medicine

Jacqueline K. Barton, Arthur and Marian Hanisch Memorial Professor and professor of chemistry and chair of the Division of Chemistry and Chemical Engineering at Caltech, has been elected to membership in the Institute of Medicine (IOM), one of the highest honors in the fields of health and medicine. As the health arm of the National Academies, the IOM is recognized as "a national resource for independent, scientifically informed analysis and recommendations on human health issues."

"The Institute of Medicine selects as members those individuals who are at the top of their fields; this is certainly true of Professor Barton," says Caltech president Jean-Lou Chameau. "This highly prestigious appointment is a reflection of the respect Professor Barton has earned among leaders in medicine, science, and academia."

"I am honored to have been elected to join this prestigious group of colleagues," says Barton. "It is also nice to consider that the research in my group, which started out as quite fundamental research, may have implications and applications that touch the medical community."

In particular, Barton's research group examines the chemical and physical properties of DNA. Her lab has made fundamental discoveries with regard to the way electrical charges travel through DNA structures. This basic research has led to the development of novel DNA diagnostics and to insights into how DNA is damaged and repaired, an important issue with respect to aging and cancer. Barton has also designed a range of transition metal complexes as probes of DNA damage.  Her work provides a foundation for the design of new chemotherapeutics.

Barton joined the Caltech faculty as a professor of chemistry in 1989 and was named Hanisch Memorial Professor in 1997. She was appointed division chair in 2009.

Barton is the recipient of numerous awards, including the National Medal of Science in 2011, as well as the American Chemical Society Award in Pure Chemistry, the National Science Foundation's Waterman Award, and a MacArthur Fellowship, among others. Barton was elected a fellow of the American Philosophical Society in 2000 and to the National Academy of Sciences in 2002.

Barton is one of 70 individuals and 10 foreign associates invited to join the IOM in 2012. Each year, the full membership of the IOM elects new members from the medical profession, research institutions, and universities. To diversify its pool of experts, a quarter of the membership is drawn from fields such as the natural, social, and behavioral sciences; law; engineering; and the humanities.

In addition to advising Congress on health-related policy matters, the IOM, which was established in 1970 by the National Academy of Sciences, generates reports to inform the public about issues as wide ranging as electronic health records, diet and obesity, AIDS treatment and prevention, and vaccine side effects. The Institute also hosts events and speaking engagements throughout the year to disseminate information on health topics and stimulate discussion.

With her election, Barton becomes the ninth member of the Caltech community (faculty and trustees) elected to the IOM.

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Caltech's Sarah Reisman Wins Arthur C. Cope Scholar Award

Sarah Reisman, assistant professor of chemistry at Caltech, is one of 10 winners of 2013 Arthur C. Cope Scholar Award from the American Chemistry Society. Winning in the "early career scholar" category, Reisman will accept the award at the annual meeting of the American Chemistry Society in Indianapolis in September 2013.

According to the award citation, Reisman was recognized for her Caltech research group's original contributions to the understanding of complex molecule synthesis and reaction development.

"It is a wonderful honor in recognition of our research program," says Reisman. "I am very proud of my students and post-doctoral fellows whose dedication and hard work helped to make this award possible."

The award includes a certificate, a $5,000 cash prize, a $40,000 unrestricted research grant, and up to $2,500 in travel expenses for Reisman to deliver a lecture at the American Chemical Society's meeting in Indianapolis next year.

 

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Caltech Again Named World's Top University in <i>Times Higher Education</i> Global Ranking

PASADENA, Calif.—The California Institute of Technology (Caltech) has been rated the world's number one university in the 2012–2013 Times Higher Education global ranking of the top 200 universities.

Oxford University, Stanford University, Harvard University, and MIT round out the top five.

"We are pleased to be among the best, and we celebrate the achievements of all our peer institutions," says Caltech president Jean-Lou Chameau. "Excellence is achieved over many years and is the result of our focus on extraordinary people. I am proud of our talented faculty, who educate outstanding young people while exploring transformative ideas in an environment that encourages collaboration rather than competition."

Times Higher Education compiled the listing using the same methodology as in last year's survey. Thirteen performance indicators representing research (worth 30 percent of a school's overall ranking score), teaching (30 percent), citations (30 percent), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators, 7.5 percent), and industry income (a measure of innovation, 2.5 percent) make up the data. Included among the measures are a reputation survey of 17,500 academics; institutional, industry, and faculty research income; and an analysis of 50 million scholarly papers to determine the average number of citations per scholarly paper, a measure of research impact.

In addition to placing first overall in this year's survey, Caltech came out on top in the teaching indicator as well as in subject-specific rankings for engineering and technology and for the physical sciences.

"Caltech held on to the world's number one spot with a strong performance across all of our key performance indicators," says Phil Baty, editor of the Times Higher Education World University Rankings. "In a very competitive year, when Caltech's key rivals for the top position reported increased research income, Caltech actually managed to widen the gap with the two universities in second place this year—Stanford University and the University of Oxford. This is an extraordinary performance."

Data for the Times Higher Education's World University Rankings were provided by Thomson Reuters from its Global Institutional Profiles Project, an ongoing, multistage process to collect and validate factual data about academic institutional performance across a variety of aspects and multiple disciplines.

The Times Higher Education site has the full list of the world's top 400 schools and all of the performance indicators.

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John Brady Wins Fluid Dynamics Prize

John Brady, Chevron Professor of Chemical Engineering and professor of mechanical engineering at Caltech, will receive the 2012 Fluid Dynamics Prize from the American Physical Society at the Division of Fluid Dynamics annual meeting in November. Brady was cited for his contributions to the study of the deformation and flow of complex fluids, for developing a computational model known as Stokesian Dynamics, and for his contributions to the field of fluid dynamics through his role as a journal editor.

"I am honored to receive this award from the American Physical Society," Brady says. "The mechanics of complex fluids is a very exciting field right now. While we gained a great deal of understanding of these materials over the past few decades, there is still so much yet to be discovered. That's what keeps me and my research group going."

 

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Showing the Way to Improved Water-Splitting Catalysts

Caltech chemists identify the mechanism by which such catalysts work

PASADENA, Calif.—Scientists and engineers around the world are working to find a way to power the planet using solar-powered fuel cells. Such green systems would split water during daylight hours, generating hydrogen (H2) that could then be stored and used later to produce water and electricity. But robust catalysts are needed to drive the water-splitting reaction. Platinum catalysts are quite good at this, but platinum is too rare and expensive to scale up for use worldwide. Several cobalt and nickel catalysts have been suggested as cheaper alternatives, but there is still plenty of room for improvement. And no one has been able to determine definitively the mechanism by which the cobalt catalysts work, making it difficult to methodically design and construct improved catalysts.

Now chemists at the California Institute of Technology (Caltech) have determined the dominant mechanism for these cobalt catalysts. Their findings illuminate the road to the development of better catalysts—even suggesting a route to the development of catalysts based on iron, an element that is plentiful and cheap and could offer part of the answer to our energy woes.

"We've worked out this mechanism, and now we know what to do to make a really great catalyst out of something that's really cheap as dirt," says Harry Gray, the Arnold O. Beckman Professor of Chemistry at Caltech and senior author of a paper that describes the findings in the current issue of the Proceedings of the National Academy of Sciences (PNAS). "This work has completely changed our thinking about which catalyst designs to pursue."

A major barrier to improving the performance of man-made catalysts has been the lack of understanding of the mechanism—the chemical pathway that such catalysts follow leading to the production of hydrogen. As with any multistep manufacturing project, chemists need to know what is involved in each reaction that takes place—what goes in, what changes take place, and what comes out—in order to maximize efficiency and yield.

Three mechanisms have been suggested for how the cobalt catalysts help make hydrogen—one proposed by a French team, one developed by Caltech researchers, including Nate Lewis and Jonas Peters, and a third suggested more recently by a former graduate student in Gray's group, Jillian Dempsey (PhD '10). Until now, no one has managed to prove definitively which mechanisms actually occur or whether one was dominant, because the reactions proceed so quickly that it is difficult to identify the chemical intermediates that provide evidence of the reactions taking place. 

These cobalt catalysts are complexes that involve the metal bound to many different functional groups, or ligands. In the current study, Caltech postdoctoral scholar Smaranda Marinescu was able to add a set of ligands to cobalt, making the reaction slow down to the point where the researchers could actually observe the key intermediate using nuclear magnetic resonance (NMR) spectroscopy. "Once we could see that key intermediate by NMR and other methods, we were able to look at how it reacted in real time," Gray says. They saw that Dempsey's mechanism is the predominant pathway that these catalysts use to generate hydrogen. It involves a key reactive intermediate gaining an extra electron, forming a compound called cobalt(II)-hydride, which turns out to be the mechanism's active species.

In a previous PNAS paper, work by Gray and lead author Carolyn Valdez suggested that the Dempsey mechanism was the most likely explanation for the detected levels of activity. The new paper confirms that suggestion.

"We now know that you have to put another electron into cobalt catalysts in order to get hydrogen evolution," Gray says. "Now we have to start looking at designs with ligands that can accept that extra electron or those that can make atomic cobalt, which already has the extra electron."

Gray's group is now working on this latter approach. Moreover, these results give his group the information they need to develop an extremely active iron catalyst, and that will be their next big focus.

"We know now how to make a great catalyst," he says. "That's the bottom line."

In addition to Marinescu and Gray, Jay Winkler, a faculty associate and lecturer at Caltech, was also a coauthor on the paper, "Molecular mechanisms of cobalt-catalyzed hydrogen evolution." The work was supported by the National Science Foundation Center for Chemical Innovation in Solar Fuels as well as Chevron Phillips Chemical.

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Learning One of Cancer's Tricks

Caltech chemists determine one way tumors meet their growing needs

PASADENA, Calif.— Behaving something like ravenous monsters, tumors need plentiful supplies of cellular building blocks such as amino acids and nucleotides in order to keep growing at a rapid pace and survive under harsh conditions. How such tumors meet these burgeoning demands has not been fully understood. Now chemists at the California Institute of Technology (Caltech) have shown for the first time that a specific sugar, known as GlcNAc ("glick-nack"), plays a key role in keeping the cancerous monsters "fed." The finding suggests new potential targets for therapeutic intervention.

The new results appear in this week's issue of the journal Science

The research team—led by Linda Hsieh-Wilson, professor of chemistry at Caltech—found that tumor cells alter glycosylation, the addition of carbohydrates (in this case GlcNAc) to their proteins, in response to their surroundings. This ultimately helps the cancerous cells survive. When the scientists blocked the addition of GlcNAc to a particular protein in mice, tumor-cell growth was impaired.

The researchers used chemical tools and molecular modeling techniques developed in their laboratory to determine that GlcNAc inhibits a step in glycolysis (not to be confused with glycosylation), a metabolic pathway that involves 10 enzyme-driven steps. In normal cells, glycolysis is a central process that produces high-energy compounds that the cell needs to do work. But Hsieh-Wilson's team found that when GlcNAc attaches to the enzyme phosphofructokinase 1 (PFK1), it suppresses glycolysis at an early phase and reroutes the products of previous steps into a different pathway—one that yields the nucleotides a tumor needs to grow, as well as molecules that protect tumor cells. So GlcNAc causes tumor cells to make a trade—they produce fewer high-energy compounds in order to get the products they need to grow and survive.

"We have identified a novel molecular mechanism that cancer cells have co-opted in order to produce intermediates that allow them to grow more rapidly and to help them combat oxidative stress," says Hsieh-Wilson, who is also an investigator with the Howard Hughes Medical Institute.

This is not the first time scientists have identified a mechanism by which tumor cells might produce the intermediates they need to survive. But most other mechanisms have involved genetic alterations, or mutations—permanent changes that lead to less active forms of enzymes, for example. "What's unique here is that the addition of GlcNAc is dynamic and reversible," says Hsieh-Wilson. "This allows a cancer cell to more rapidly alter its metabolism depending on the environment that it encounters."

In their studies, Hsieh-Wilson's team found that this glycosylation—the addition of GlcNAc to PFK1—is enhanced under conditions associated with tumors, such as low oxygen levels.  They also found that glycosylation of PFK1 was sensitive to the availability of nutrients. If certain nutrients were absent, glycosylation was increased, and the tumor was able to compensate for the dearth of nutrients by changing the cell's metabolism.

When the researchers analyzed human breast and lung tumor tissues, they found GlcNAc-related glycosylation was elevated two- to fourfold in the majority of tumors relative to normal tissue from the same patients. Then, working with mice injected with human lung-cancer cells, the researchers replaced the existing PFK1 enzymes with either the normal PFK1 enzyme or a mutant form that could no longer be glycosylated. The mice with the mutant form of PFK1 showed decreased tumor growth, demonstrating that blocking glycosylation impairs cancerous growth.

The work suggests at least two possible avenues for future investigations into fighting cancer. One would be to develop compounds that prevent PFK1 from becoming glycosylated, similar to the mutant PFK1 enzymes in the present study. The other would be to activate PFK1 enzymes in order to keep glycolysis operating normally and help prevent cancer cells from altering their cellular metabolism in favor of cancerous growth.

Hsieh-Wilson's group has previously studied GlcNAc-related glycosylation in the brain. They have demonstrated, for example, that the addition of GlcNAc to a protein called CREB inhibits the protein's ability to turn on genes needed for long-term memory storage. On the other hand, they have also shown that having significantly lower levels of GlcNAc in the forebrain leads to neurodegeneration. "The current thinking is that there's a balance between too little and too much glycosylation," says Hsieh-Wilson. "Being at either extreme make things go awry, whether it's in the brain or in the case of cancer cells."

Additional Caltech coauthors on the paper, "Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism," were lead author Wen Yi, a postdoctoral scholar in Hsieh-Wilson's group; Peter Clark, a former graduate student in Hsieh-Wilson's group; and William Goddard III, the Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics. Daniel Mason and Eric Peters of the Genomics Institute of the Novartis Research Foundation and Marie Keenan, Collin Hill, and Edward Driggers of Agios Pharmaceuticals were also coauthors.

The work was supported by the National Institutes of Health, the Department of Defense Breast Cancer Research Program, and a Tobacco-Related Disease Research Program postdoctoral fellowship.

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Caltech Chemist Wins ASBMB Young Investigator Award

The American Society of Biochemistry and Molecular Biology (ASBMB) named Caltech chemistry professor Shu-ou Shan a recipient of the 2013 Young Investigator Award. The award will be presented at the ASBMB annual meeting in Boston next April.

Shan was recognized for her research that addresses how "a novel class of nucleotide hydrolases drives the efficient and accurate delivery of newly synthesized proteins to their correct destinations."

"This award would not have been possible without the support from my subgroup and division and all the wonderful Caltech students and postdocs who work so hard," says Shan.

"We are extremely happy that ASBMB has selected Shu-ou Shan for the Young Investigators Award," said Jacqueline Barton, Arthur and Marian Hanisch Memorial Professor, professor of chemistry, and chair of the Division of Chemistry and Chemical Engineering at Caltech. "It is a testament to the hard work and dedication of Shan and her team here at Caltech."

Shan's research interfaces between chemistry and biology to understand fundamental cellular processes at the level of chemical and physical principles. More information about Shan's research group at Caltech can be found at http://shangroup.caltech.edu.

The ASBMB Young Investigator Award recognizes outstanding research contributions to biochemistry and molecular biology. The recipient must have no more than 15 years postdoctoral experience. Nominations for these awards are made by ASBMB members, but nominees need not be members. The award consists of a plaque, $5,000, transportation, and expenses to present a lecture at the 2013 ASBMB annual meeting.

 

 

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