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The research group of Professor Steven Kass (MSI Fellow, Chemistry) uses MSI resources in their investigations into hydrogen bond networks. The goal of this research is to understand enzyme catalysis and develop hydrogen bond catalysts, novel acids and bases, and molecular anion receptors. By mimicking nature, the researchers have found that hydrogen bond arrays stabilize charged centers to a greater degree than was previously recognized and that flexible alcohols can serve as anion receptors. The Kass group has published results of their research in several articles that appeared in the Journal of the American Chemical Society during 2012 and 2011:
- “Three Hydrogen Bond Donor Catalysts: Oxyanion Hole Mimics and Transition State Analogues,” EV Beletskiy, J Schmidt, XB Wang, and SR Kass, JACS:134(45):18534, DOI:10.1021/ja3085862 (2012)
- “Characterization of a Saturated and Flexible Aliphatic Polyol Anion Receptor,” A Shokri, J Schmidt, XB Wang, and SR Kass, JACS 134(41):16944, DOI:10.1021/ja3075456 (2012)
- “Effect of Hydrogen Bonds on pKa Values: Importance of Networking,” A Shokri, A Abedin, A Fattahi, and SR Kass, JACS 134(25):10646, DOI:10.1021/ja3037349 (2012)
- "Hydrogen Bonded Arrays: The Power of Multiple Hydrogen Bonds," A Shokri, J Schmidt, XB Wang, and SR Kass, JACS 134(4):2094, DOI:10.1021/ja2081907 (2011)
The group is modeling a number of polyols and comparing their thermodynamic properties and binding properties with different substrates. This work benefits from the use of the supercomputers because the molecules are large and flexible, which makes it computationally expensive to examine them. The catalyst-substrate complexes also involve very time-consuming calculations. Current research in 2013 involves modeling infrared spectra and electron binding energies of a number of deprotonated polyols (the conjugate bases of Bronsted acids) and polyol-substrate complexes (bound hydrogen bond catalysts). This work complements experimental efforts that entail synthesizing novel “green” acids, hydrogen bond catalysts, and hosts for molecular recognition, as well as probing their reactivities and properties (e.g. pKa’s), and examining their binding via mass spectrometry experiments (e.g. electron affinity measurements and IR spectra determinations of bound catalysts).
Description of image: The difference in the acidity of the two compounds shown is 21 orders of magnitude (i.e., 1021, a very large number!), due to the hydrogen bond network in the larger species. To put this number into context, it corresponds to the weight of an elephant (more precisely, a male African elephant) versus that of the entire world. That is, the ratio of the weight of the world to that of an elephant is the same as the ratio of the acidity difference of the polyol to the simple alcohol.
MSI PI Alexander Heger (Physics) and Ph.D. student Ke-Jung (Ken) Chen use MSI resources to study and model pulsational pair-instability supernovae. In this form of supernova, a massive star expells “shells” of matter on a time-scale of years. The shells interact and collide with each other, converting kinetic energy into visible light.
A recent issue of Nature included an article by Professor Heger explaining this phenomenon and discussing observations by Eran Ofek (Weizmann Institute of Science, Rehovot, Israel) and his colleagues of a massive star shortly before it went supernova. The article is accompanied by a dramatic simulation visualization of shell collisions produced by Mr. Chen.
The Heger group’s investigations into these pulsational pair-instability supernovae include the use of CASTRO, which is a three-dimensional adaptive mesh refinement code. Using Itasca, the researchers are able to create visualizations of the interaction of stellar materials. Other areas of study by this group include simulations of Type 1 X-ray bursts and numerical simulation of the first binary star in the universe, including radiation feedback and supernova simulation.
Mr. Chen was a Finalist in the 2010 MSI Research Exhibition poster competition and was the Grand Prize winner at the 2011 competition. MSI highlighted this research in the Spring 2011 MSI Research Bulletin. Professor Heger and his colleagues published another recent article concerning supernova explosions in December 2012 in the Astrophysical Journal (“New Two-Dimensional Models of Supernova Explosions by the Neutrino-Heating Mechanism: Evidence for Different Instability Regimes in Collapsing Stellar Cores,” Astrophysical Journal, 761(1): 72, DOI:10.1088/0004-637X/761/1/72 (2012)).
(Left): A simulation of a collision between two shells of matter ejected by a massive star in two subsequent pulsational pair-instability supernova eruptions, only years apart, just before the star dies. Displayed is a slice through the upper-right corner of the event. The radius of the shell that contains collision fragments (red knots) is about 500 times the Earth–Sun distance. The color coding represents gas density ranging from 10−11 to 10−16 grams per cubic centimeter, with red indicating the highest density and dark blue the lowest.
(Right): Close-up of fluid instabilities; these can grow to a large scale and destroy the “onion” structure of stars leading to the mixture of the ejecta.
MSI researchers presented posters of their work at the 2013 MSI Research Exhibition on Thursday, April 11, 1:00-3:30 p.m., on the fourth floor of Walter Library. This was the fourth year that MSI held this event.
Poseted were judged by a panel of MSI Principal Investigators and prizes were awarded. Posters competed in one of two categories, Physical Sciences and Engineering or Biological and Medical Sciences. Entrants were from a wide variety of disciplines.
Light refreshments were served. More information, including photos of the event, can be found on the 2013 Research Exhibition webpage.
The pictures above were taken at the 2012 MSI Research Exhibition.
Associate Professor Kylie Walters received her Ph.D. in Biophysics from Harvard University. She joined the faculty of the University of Minnesota in 2002 and is in the Department of Biochemistry, Molecular Biology, and Biophysics. Professor Walters recently talked with an MSI staffer about her research and work with MSI.
MSI: How long have you been using MSI to support your research work?
Kylie Walters: I have been using MSI resources since I first came to the University of Minnesota, in 2002.
MSI: Could you talk a little about your research on ubiquitin signaling, what the goals of the research are?
KW: Ubiquitin signals are used for a large breadth of cellular events. Their most well-known use is to target proteins for degradation, including mis-folded or damaged proteins, or healthy ones that need to be removed under certain cellular conditions. Failure in ubiquitin signaling pathways is associated with cancer, neurodegenerative diseases, viral infection, and even diabetes.
MSI: How have MSI’s resources contributed to your research?
KW: My group uses structural biology tools to solve protein structures, characterize their dynamic behavior, and understand how they interact with each other. What we hope to obtain from this is a better understanding of protein signaling pathways, and ultimately to find new targets related to carcinogenesis and neurodegenerative diseases. Our most powerful technique is NMR spectroscopy, and we use MSI to process and analyze all of our NMR data. Specifically we use Itasca for our high-performance computational needs. Without Itasca some of our structural calculations would take a very long time. As we progress we try to characterize bigger and bigger complexes; consequently the calculation becomes larger as well. These calculations are greatly facilitated by parallel processing and supercomputing.
My group has also used MSI to help us procure various pieces of software. MSI also helped implement an on-site PDB (protein data bank). So now everything from the PDB is here in our lab. For example, we use a molecular modeling program called Rosetta. Rosetta is very good at taking a limited amount of information on a specific protein, then using the whole database of solved structures to come up with a model structure for that protein. This makes difficult proteins easier to analyze and you can access some structural data fairly quickly. Running Rosetta through the web can require greater than one month of waiting time, whereas, when we use MSI resources, we get results within a day.
MSI: How have your undergraduate and graduate students benefited from working with MSI?
KW: The facilities that MSI offers as well as their computer-savvy staff have been valuable resources in helping my graduate students to move their projects forward. I have also had undergraduate students participate in the MSI summer research program. The program gave the students a unique exposure to a much broader scope of research than in the lab. My students also go to the tutorials offered at MSI. The tutorials have been very useful.
MSI: Have any particular MSI staff members been critical to the success of your research efforts?
KW: Yuk Sham was very helpful in the area of molecular modeling when he was at MSI and we even co-authored a paper together [Editor’s note: Dr. Sham is currently Assistant Director of the Center for Drug Design as well as an MSI Principal Investigator]. My students have also worked with Nancy Rowe [Scientific Computing Consultant and Manager of the BSCL and BMSDL]. For example, graduate student Aaron Ehlinger worked with Nancy to get programs and software up and running. In many cases MSI will optimize source codes for software that we use in the BSCL.
MSI: How might MSI prepare to provide the cutting-edge support you’ll need going forward? For example, software applications or staff competencies we might add?
KW: I really feel like your support, software, and hardware have been fantastic. We are all around happy with our experience with MSI.
Description of Figure: Structure of proteasome ubiquitin receptor Rpn13 calculated by XPLOR-NIH version 2.24 in the MSI Basic Sciences Computing Laboratory. 347 paramagnetic relaxation enhancement distance constraints (dashed lines) were used to define inter-domain interactions between Rpn13's ubiquitin binding domain (orange) and its Uch37-binding domain (blue).
Description of figure: An example of a hexadehydro-Diels-Alder cascade (1 to 3). Simple triyne substrates like 1 cycloisomerize to reactive benzyne intermediates like 2, which are then captured by various trapping agents (in this example, an internal silylether) to produce structurally complex benzenoid products like 3.
The research group of Professor Thomas Hoye (Chemistry) uses MSI for their investigations of the thermodynamics of reactions involving the highly reactive organic species benzyne. Benzynes (cf. 2 in graphic above) are widely studied because their reactions with other chemical substances are very useful. The resulting compounds (cf. 3, “benzenoid products”) are useful in the development and synthesis of pharmaceutical drugs, agrochemicals, dyes, and polymers.
Related to this work, the Hoye group recently published some interesting and unexpected results in the prestigious journal Nature. This paper describes the generality of a fundamentally new reaction: the hexadehydro-Diels-Alder reaction (“The Hexadehydro-Diels-Alder Reaction,” Nature, DOI: 10.1038/nature11518, 2012). This chemistry generates ortho-benzyne by a simple metal- and reagent-free thermal cycloisomerization of a triyne precursor (cf 1). This is important because metals and other reagents can affect the subsequent chemical trapping reactions of the benzyne (e.g. 2 to 3). Many new types of reactions have been discovered with this new strategy for benzyne synthesis. These are both synthetically useful and mechanistically interesting.
The group is now using MSI to understand these new reactivities from the computational perspective. They are using density functional theory (DFT) calculations to study both the thermodynamics and the transition structures of various stages of the overall process. They don’t yet completely understand the mechanism of the hexadehydro-Diels-Alder reaction itself, and the DFT calculations are being used to complement the group’s experiments. One main goal is to determine whether the reaction is stepwise (cf. 4b), proceeding through diradical intermediates (as has been suggested in other systems) or concerted (cf. 4a, which is suggested by experiments). If the reaction is, in fact, concerted, it will be compatible with radical-sensitive substrates, which increases the overall synthetic utility. Similar questions about the concerted (cf. 5a) vs. stepwise (cf. 5b) nature of the benzyne trapping steps (cf. 2 to 3) are also being explored through computation.