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Scientists are now using computers to help discover new drugs. Researchers at the University’s Center for Drug Design are in the forefront of these efforts. Professor Yuk Sham and his research group are studying the molecular recognition process of how molecules selectively associate with one another. Understanding the specific interactions involved is important for identifying and designing new drugs that can inhibit the normal function of viral proteins and stop the proliferation of viruses.
HIV/AIDS is an incurable disease. With the continuing emergence of drug resistance, it is extremely important to continue developing new drugs for the long-term management of the HIV/AIDS patients. Dr. Sham and his group, working closely with other members of the Center for Drug Design, use MSI high-performance computing clusters to develop accurate structural models to better understand these interactions to design a better inhibitor for the discovery and development of new antiviral drugs. The image above shows the structural model of HIV integrase developed by Professor Sham's research group. It is an essential viral enzyme that incorporates the HIV genome into human DNA. Effective inhibition of this enzyme is one of the validated approaches for the effective treatment of HIV/AIDS.
Dr. Sham’s group has also created videos describing the drug-development process against HIV/AIDS. They can be seen on YouTube:
"Targeting HIV Replication” (3:02 min)
"Making of an AIDS Drug” (2:26 min)
Protein kinase A (PKA) is involved in many cellular events and its activity can be tweaked and compartmentalized through mirystoylation of its N-terminus. (Mirystoylation is a type of protein modification that plays a role in directing and anchoring proteins to membranes and, thus, is involved with cellular regulation, signal transduction, and apoptosis.)
Research Associate Dr. Alessandro Cembran, who works with MSI PIs Professor Gianluigi Veglia (Biochemistry, Molecular Biology, and Biophysics) and Professor Jiali Gao (MSI Fellow, Chemistry), presented a poster at the 2012 MSI Research Exhibition about research he, Professors Veglia and Gao, and Research Associate Dr. Larry Masterson performed concerning PKA. The PKA catalytic subunit (PKA-C) mediates the transfer of the γ-phosphate group from ATP to threonine or serine residues. PKA activity must be tightly controlled in time and space, and myristoylation of its N-terminus is a regulatory mechanism that is not yet fully understood. The research presented in the poster investigated the short- and long-range structural and dynamical effects of PKA-C N-myristoylation through a combined experimental and computational approach. The group uses MSI resources to perform structural modeling and molecular dynamics simulations of cardiac proteins in their native lipid environment.
The results showed that myristoylation induces changes in structure and dynamics of the residues surrounding the myristoyl group, as well as long range perturbations involving catalytically relevant residues.
The image above shows the structure of the myristoylated kinase. Highlighted in the box is the allosteric link, responsible for the transmission of the allosteric signal from the myristoyl group to the active site. On the right, distance matrix analysis allows to identify regions in close contact.
MSI, with the support of the University of Minnesota’s NTS (Network and Telecommunication Services), has recently deployed a system to take advantage of the ten-gigabit network known as the Northern Lights GigaPoP network. With this system in place, MSI was able to help Peter J. Mendygral, a post-doctoral member of MSI principal investigator Tom Jones’s research group and employee of Cray, with some important work. Pete needed to transfer about seven terabytes of data in less than two days. He was able to do this successfully by utilizing MSI’s high-performance TeraScala storage system to store his remote data and using Globus GridFTP software to effect the transfer. Pete sat down with a MSI staffer to talk about his research, experience with MSI, and how MSI resources have helped him succeed.
MSI: What type of research are you doing?
Pete: My research is in astrophysics. I study magnetohydrodynamics, which means fluid dynamics simulations of ionized plasma with magnetic fields and their effects. I also study what we understand to exist in galaxy clusters, which are the largest gravitationally bound systems in the universe. So, specifically what I look at are the interactions between outflows of supermassive black holes that we believe exist at the centers of some of the large galaxies in these galaxy clusters. Within these galaxies are black holes that emit jets, supersonic jets. On a very large scale, they can have an enormous influence on the evolution of the clusters as well as the individual galaxies and stars.
MSI: What resources previously and currently have you utilized here at MSI?
Pete: Primarily we’ve run these simulations of jets and galaxy clusters on Itasca. I’ve also focused on other more specific phenomena, like the build-up of magnetic fields in galaxy clusters and the creation and evolution of cosmic ray particles. We have also done some smaller, kind of one-off type of things mainly for verifying the codes that I have written. Collaborators and I have done simulations of solar wind, galactic super bubbles, and giant bubbles created in galaxies by supernovas. My primary focus has been on the outflows of black holes and galaxy clusters, in terms of the simulations I have run on MSI systems. In addition, I use the LMVL systems a lot for my movie creations. In the LMVL I do a lot of stereo renderings because it really gives me an edge in understanding what’s going on inside a simulation. Seeing that third dimension is critical for understanding these simulations.
MSI: How has your use of the Northern Lights GigaPoP network in coordination with MSI systems and our high-performance TeraScala storage system enhanced your capabilities as a researcher?
Pete: I did my simulation this particular time on the Kraken system [the image above is from that simulation] at the National Institute for Computational Science (NISC) in Tennessee and it produced around seven terabytes of data. It’s often taken for granted in high-performance computing that you can produce your calculation relatively quickly, but then you come across the problem of dealing with this enormous dataset, especially when you run your simulation at a non-local site. So getting it in-house for analysis and creating movies become difficult challenges. The traditional route would be to send a secured copy via remote access (i.e. the ‘scp’ command), but this process would have taken at least 90 days. In this particular instance I had a conference coming up in a couple of weeks and I needed the data as soon as possible. So, 90 days was not going to work for me. The other option was to try to coordinate someone on the other end filling up a large number of hard drives and manually mailing them to me. That would require a large personnel cost and, best-case scenario, it would have still taken about two weeks. So what MSI’s Jeff McDonald and David Porter did for me was set up an MSI hardware interface with the Northern Lights GigaPoP network and I was able to move the entire dataset in less than two days. Because of this I was able to start working on my data immediately. This is an absolutely critical ability to have.
With the ever-changing needs of our users, MSI is proud to be able to help meet their challenges and to support researchers like Pete Mendygral in his pursuit of cutting edge research.
Deep brain stimulation (DBS) is a surgical therapy used to treat many neurological disorders that are refractory to medication. Patients with severe Parkinson’s disease, dystonia, essential tremor, obsessive-compulsive disorder, and depression have all benefited from DBS. The therapy involves implanting small electrodes in brain regions that exhibit pathological activity, and then stimulating those regions with continuous pulses of electricity. One of the ongoing challenges with this therapy is how to best minimize damage to brain tissue during the electrode implantation process.
Ben Teplitzky and Allison Connolly, student researchers in the group of Assistant Professor Matt Johnson (Biomedical Engineering), presented a poster at the 2012 MSI Research Exhibition on a project developing DBS electrodes that can be implanted within arterial and venous vessels of the brain. With the support of MSI resources, the Johnson group has developed three-dimensional models of the cerebral vasculature and coupled them with computational neuron models of DBS. These models now enable researchers to prospectively evaluate and optimize electrode geometries and targeting strategies for endovascular deep brain stimulation, as shown in the figure above.
Minnesota Supercomputing Institute (MSI) Provides Modeling and Analysis Support for Development of INVELOX, A Wind-Generated Energy Technology Developed by SheerWind, Inc.
SheerWind, Inc., a Minnesota-based company, has been developing novel approaches for generating electric power from the wind. In the fall of 2011, SheerWind contracted MSI to do an independent study of their new INVELOX tower, which is designed to channel and focus wind kinetic energy. MSI generated high-resolution computational fluid dynamic (CFD) simulations for this analysis. To achieve sufficient accuracy these simulations were performed on high-resolution computational meshes. The simulations were performed using Itasca’s high-performance computing (HPC) resources. These models produced the detailed air flow and pressure information needed to assess the INVELOX tower’s ability to channel and focus wind power. This work lead to the development of custom software for generating the solid geometry of a wide class of structures, as well as assembling and tuning a suite of software tools for massively parallel CFD computations on MSI’s HPC resources. Potential uses for this suite of software on MSI’s HPC systems include parameter space searches for optimal wind tower design and, on a much large scale, modeling air flow over terrain for optimal siting of wind towers. The image above shows streamlines viewed from the top of an INVELOX tower.
MSI is an authorized External Sales Organization of the University of Minnesota, which allows it to sell services to parties outside the University, including access to its supercomputing facilities, technical consulting, and training. MSI is currently working with a number of different firms and looks to develop relationships with additional parties.