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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.
Understanding the Biophysics of Parkinson’s Disease: Modeling Interactions Between α-Synuclein and Cellular Membranes
The research group of Assistant Professor Jonathan Sachs (Biomedical Engineering) uses MSI for their study of the behavior of proteins and membranes. Mutations in one particularly interesting and important protein, α‐Synuclein (αS), are associated with Parkinson’s disease (PD), a common neurodegenerative disorder that affects 1% of Americans over the age of 65. The pathology of PD involves the selective loss of dopaminergic neurons and the presence of dense, spherical cytoplasmic inclusions, known as Lewy bodies, in the substantia nigra. αS is a 140 amino acid, natively unfolded protein that is the primary component of the fibrillar aggregates that make up Lewy bodies. The precise role of αS in the pathology of PD remains unclear. However, findings in early-onset PD patients, namely the identification of three rare autosomal dominant mutations, along with incidences of multiplication of the αS gene, have established that αS is critical to the progression of the disease.
In its normal state, αS is abundantly expressed in neurons, where some of it is localized to the pres-synaptic nerve endings and binds tightly to synaptic vesicles. The native function of αS is poorly understood, although some evidence suggests that it may play a role both in maintaining neuronal plasticity and in the regulation of synaptic vesicle recycling. It has also been proposed that interactions of specific aggregated states of αS with cellular membranes may be a mechanism of cytotoxicity in PD. Because both its normal function as a synaptic vesicle-associated protein, as well as its proposed pathological function in PD, likely involve interactions with cellular membranes, a complete characterization of the nature of αS/membrane interactions is of great interest. Understanding these interactions is a principle goal of the Sachs lab, and a combined computational and experimental strategy that brings together resources from MSI and the University of Minnesota’s Characterization Facility is being pioneered by Sachs’s PhD student, Anthony Braun.
It has recently become clear that amphipathic α‐helices, like αS, act by wedging between lipid headgroups and causing the membrane to curve, a morphological change necessary for a lipid vesicle to either bud or fuse. Many such proteins have been studied for their ability to cause gross‐deformations in vesicles (see the figure, above), namely the formation of lipid tubes (tubulation) or smaller vesicles (vesiculation). Theories have suggested that a helix must be sufficiently long and bind at a specific depth within the phospholipid bilayer in order to affect these changes.
The Sachs group is developing very large molecular simulations of amphipathic α‐helices bound to membranes in order to establish the relative importance of each of these attributes, as well as the contribution of helical flexibility, which this group has recently shown to contribute to membrane curvature in a unique way. The group is testing the hypothesis that the essential properties of a curvature‐inducing α‐helix, like αS, are not uniquely encoded in the primary sequence, but instead result from the sum of the protein’s physical attributes (length, hydrophobicity and flexibility). This research involves molecular dynamics computations on the supercomputers and results have been published recently in the Journal of the American Chemical Society (“alpha-Synuclein Induces Both Positive Mean Curvature and Negative Gaussian Curvature in Membranes,” A.R. Braun, E. Sevcsik, P. Chin, E. Rhoades, S. Tristram-Nagle, and J.N. Sachs, J Am Chem Soc 134, 2613-2620 (2012), DOI:10.1021/ja208316h) and the Journal of Biological Chemistry (“Curvature Dynamics of Alpha-Synuclein Familial Parkinson Disease Mutants: Molecular Simulations of the Micelle- and Bilayer-Bound Forms,” J.D. Perlmutter, A.R. Braun, and J.N. Sachs, J Biol Chem 284, 7177-7189 (2009), DOI:10.1074/jbc.M808895200).
Other work from the Sachs lab on the Tumor Necrosis Factor receptors has also utilized the MSI resources, and focuses on understanding conformation changes in these proteins to establish new therapeutic strategies for cancer and auto-inflammatory disease (“TNFR1 Signaling Is Associated With Backbone Conformational Changes of Receptor Dimers Consistent With Overactivation in the R92Q TRAPS Mutant,” A.K. Lewis, C.C. Valley, and J.N. Sachs, Biochemistry 51, 6545-6555 (2012), DOI:10.1021/bi3006626) and “Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Induces Death Receptor 5 Networks That Are Highly Organized,” C.C. Valley, A.K. Lewis, D.J. Mudaliar, J.D. Perlmutter, A.R. Braun, C.B. Karim, D.D. Thomas, J.R. Brody, and J.N. Sachs, J Biol Chem 287, 21265-21278 (2012), DOI:10.1074/jbc.M111.306480).
Figure Description: Building on their recent study that characterized the curvature fields induced in membranes by α-Synuclein (J Am Chem Soc 134, 2613-2620 (2012), DOI:10.1021/ja208316h), and relying upon the immense computational power of MSI, the Sachs group is running massive coarse-grained molecular dynamics simulations in order to study remodeling of the membrane by the protein. Shown is a snapshot with α-Synuclein (yellow beads) sitting atop a curved membrane (blue and pink beads). Water has been excluded from the image. The simulation was started with a flat membrane, but after 1 microsecond of calculated dynamics the curvature has become clear. The membrane is comprised of more than 50,000 fully hydrated lipids, requiring more than 4x106 total beads. Periodic images are included to illustrate the global topography (green beads). For these massive molecular simulations, the group takes advantage of MSI’s Itasca cluster, operating on 1024 cores (128 nodes, 8 processors per node), and achieving approximately 250 nanoseconds per 24-hour window.