SI2009 Computational seminar series

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Cyberinfrastructure for Personalized Medicine

Joint Opening Plenary Session and Computational Seminar Series

Fung Auditorium, PFBH Aug 3 - 7, 2009 12:00 - 2:15 pm

Joint Opening Plenary Session Aug 3, 2009

  • 12:15 pm Working Lunch
  • 12:30 pm Overview and Logistics: Wilfred Li, Ph.D., Teri Simas
  • 12:40 pm Group Photo
  • 12:50 pm Building Cyberinfrastructure for Biomedical Research and Personalized Medicine, Peter W. Arzberger, Ph.D., Director, NBCR

Computational Seminar Series Aug 3 - 7, 2009

  • 1:00 pm to 2:15 pm Open to all

Aug 3: Computer Aided Drug Design

Host: Andy McCammon, Ph.D., co-host: Robert Konecny, Ph.D.

Virus maturation: A paradigm for nanometer-scale protein dynamics

Jack Johnson, Ph.D., Dept. of Mol Biol., TSRI

Abstract The vast majority of activities within the cell (e.g. signaling, molecular trafficking and membrane dynamics) are based on multi-protein complexes with a transient existence. The weak interactions stabilizing these associations allow their assembly and disassembly with the proper kinetics and without the formation of “trapped” complexes. Indeed, the dominant feature of these organizations is the fragility of the association, making them difficult to investigate with biophysical methods. Most viruses are a novel association of protein and nucleic acid that initially are comparable to a cellular complex, but then achieve an exceptional level of stability in order to survive the extra-cellular environment. This transition corresponds to a program of protein dynamics encoded in the initial fragile assembly. Arrested at the first assembly stage (called a procapsid), the complex can be easily disassembled and reassembled. Given the normal virus life-cycle, the procapsid will go though a large-scale reorganization, making it robust, infectious and able to withstand harsh environments. We investigated this process in a dsDNA bacteriophage (HK97) particle and in an RNA virus (NV) capsid. Virus-like particles were made by employing recombinant expression of one (NV) or two (HK97) viral genes, allowing maturation to be studied in vitro with a variety of biophysical methods. While achieving the same biological outcome, the programs for maturation are totally different in the two particles. HK97 alters the particle energy landscape through a “scaffolding” polypeptide and a viral protease, such that initial maturation is an exothermic particle expansion followed by a “Brownian ratchet” mechanism to fully mature the particle. NV employs a low pH cue to mature the particle followed by an autocatalytic subunit cleavage that confers infectivity and remarkable stability. Experiments over the last decade provide a detailed mechano-chemical mechanism for these processes.


  1. HK97 Wikoff, W. R., Conway, J. F., Tang, J., Lee, K. K., Gan, L., Cheng, N., Duda, R. L., Hendrix, R. W., Steven, A. C., and Johnson, J. E. 2006. Time-resolved molecular dynamics of bacteriophage HK97 capsid maturation interpreted by electron cryo-microscopy and X-ray crystallography. J Struct Biol 153:300-6.
  2. Lee, K. K., Gan, L., Tsuruta, H., C., M., Conway, J. F., Duda, R. L., Hendrix, R. W., Steven, A. C., and Johnson, J. E. 2008. Virus capsid expansion driven by the capture of mobile surface loops. Structure 16:1491-1502.
  3. Gertsman, I., Gan, L., Guttman, M., Lee, K., Speir, J. A., Duda, R. L., Hendrix, R. W., Komives, E. A., and Johnson, J. E. 2009. An unexpected twist in viral capsid maturation. Nature 458:646-651.
  4. NwV Matsui, T., Lander, G., and Johnson, J. E. 2009. Characterization of large conformational changes and autoproteolysis in the maturation of a T=4 virus capsid. J Virol 83:1126-34.
  5. Tang, J., Lee, K., Bothner, B., Baker, T. S., Yeager, M., and Johnson, J. E. 2009. Dynamics and Stability in Maturation of a T=4 Virus. J Mol Biol submitted

Biographical Sketch John E. Johnson obtained a BA in Chemistry from Carthage College, Kenosha, Wisconsin in 1967 and his Ph.D. in Physical Chemistry at Iowa State University in 1972. He worked in structural virology as a post doctoral associate with Michael Rossmann at Purdue University from 1972 to 1978 and was on the faculty at Purdue from 1978 to 1995 studying the structure of viruses with crystallography. In 1995 Johnson moved to the Molecular Biology Department at the Scripps Research Institute in La Jolla, California. There his research includes virus particle dynamics studied by mass spectrometry, cryoEM and spectroscopy as well as crystallographic studies of viruses infecting yeast and bacteria. Johnson has over 260 publications that cover, the structure (at near atomic resolution) and function of 16 different viruses, as well as cryoEM and solution x-ray scattering studies of particle dynamics

Computer-aided Drug Discovery for Infectious Diseases

J. Andrew McCammon, Ph.D., Dept. of Chem. and Biochem., UCSD

Abstract The selective character of the binding and reactivity of key biological molecules is essential for life. Properly understood, such selectivity can be exploited in the design of drugs, novel antibodies or enzymes, sensors, or a host of other materials or devices. This talk will provide a brief overview of how computer simulations can be used quantitatively to interpret the selectivity of molecular behavior. Particular emphasis will be placed on proper accounting of the flexibility of the receptor in the design of ligands. Images and animations related to this work can be found at the website

Aug 4: Mesoscale Modeling

Host: Zeyun Yu, Ph.D., co-host: Rick Lawrence, Ph.D., Anushka Michailova, Ph.D.

Patient-Specific Modeling of Structure and Function of Cardiac Cells

Frank Sachse, Ph.D., Dept. of Bioengineering, U. Utah

Abstract Patient-specific modeling aims at providing insights into disease mechanisms, predicting courses of diseases, and devising appropriate therapies for these diseases. In this talk, two approaches for patient-specific modeling at cellular level are described. The first approach is based on imaging of micro-structure of cardiac tissues and cells using confocal microscopy. Several major diseases are associated with changes of microstructure, for instance hypertrophy, infarction and ischemia. Recently, catheter-based confocal imaging systems have been developed, which allow for in vivo imaging of tissue and to characterize its micro-structure. We will describe a novel method to locally introduce fluorescent dyes into living cardiac tissue. The introduction of dye is a prerequisite for confocal imaging. We will present structural models of cells and tissues applying this method together with techniques of digital image analysis to preparations of living hearts and tissue sections. In the second part of the talk, we will describe approaches for patient-specific electrophysiological modeling of cardiac cells. Various cardiac diseases are caused by mutations of proteins such as ion channels. Expression systems and patch-clamp methods allow for functional characterization of these mutations. Patient-specific models are developed by integration of these data into electrophysiological models of cardiac cells. Our studies of L-type calcium, Kir 2.1 and KCNQ1 channel mutations will exemplify this approach.

Biography Frank B. Sachse received the Dipl.-Inform. degree in computer science in 1992 and Dr.-Ing. degree in electrical engineering in 1997 from the Universität Karlsruhe (TH), Germany. In 2002, he habilitated in biomedical engineering with the thesis “Mathematical Modeling of the Mammalian Heart”. Since 2004, he is research assistant professor in bioengineering and investigator at the Nora Eccles Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, USA. His laboratory applies computational and experimental approaches to gain insights into structure and function of tissues, cells and proteins of the normal and diseased heart. Current research foci are on confocal microscopic imaging of tissues and cells, computational modelling and experimental studies of electrical signalling in cardiac tissue, and modelling of ion channels and drug binding. His publications include more than 150 peer-reviewed articles and 3 books. He organized the workshop Computer Models of the Heart (CardioModel) in 2000 in Karlsruhe, Germany, and the conference on Functional Imaging and Modelling (FIMH) in 2007 in Salt Lake City, USA. He taught courses on biomedical engineering, modelling and simulation of the cardiovascular system, and medical imaging at universities in Germany, Finland, Spain and the USA.

Multiscale modeling of nanoscale emulsions for cancer diagnosis and therapy

Sungjoo Lee, Ph.D., on behalf of Nathan Baker, Ph.D., Dept. of Biochem and Biophys, WUSTL

Aug 5: Computational Heart Electrophysiology

Host: Andrew McCulloch, Ph.D, co-host: Roy Kerckhoffs, Ph.D.

Clinical Cardiac Electrophysiology

Sanjiv Narayan, M.D., Ph.D., School of Medicine, VA Medical Center, UCSD

Towards predictive modeling of cardiac resynchronization therapy

Roy Kerckhoffs, Ph.D., NBCR, Dept. of Bioengineering, UCSD

Abstract Heart failure (HF) is a condition when the heart fails to keep up with the amount of blood that is demanded by the body. Additional abnormalities – on top of the disorder that caused failure – may worsen cardiac function. In dilated cardiomyopathy, the ventricular walls become thinner, cavities enlarge and venous pressures increase, accompanying changes at the cellular level. Patients with HF and dyssynchronous mechanical contraction have among the worst overall prognosis and left ventricular (LV) dysfunction of all HF patients. These patients can often see significant clinical and functional improvement following cardiac resynchronization therapy (CRT). CRT requires that a pacing lead is placed in the left ventricular venous anatomy along with leads in the right ventricle and right atrium. This form of ventricular pacing is used to restore a more synchronous mechanical activation pattern.

However, 30% of patients receiving a CRT system do not respond. Moreover, there are no well-defined criteria for predicting outcomes or selecting pacing sites and protocols. A new approach to CRT – and to medicine in general – might arise from the maturation of computational biology. During the last five to ten years, improvements in diagnostic medical technologies such as multi-slice cardiac CT imaging and 3-D electroanatomic mapping, combined with more powerful computing and more accurate predictive models have made it increasingly feasible to begin developing multi-scale patient-specific models that may help inform diagnosis, guide therapy or surgery, and predict outcomes, at least acutely. This presentation will focus on patient-specific computational modeling of cardiac electromechanics, applied to CRT. Recent advancements will be presented regarding the acquisition of patient-specific geometrical, electrophysiological and mechanical properties.

Biography Roy earned his M.S. degree in mechanical engineering in 1998 and his Ph.D. degree in biomedical engineering in 2003 at Eindhoven University of Technology in the Netherlands. He is working as a Project Scientist at the Cardiac Mechanics Research Group at the University of California San Diego. His research interests include multiscale modeling of cardiovascular mechanics and electrophysiology. Currently, his main focus lies on the development of multi-scale (animal-specific and patient-specific) computational models of cardiac electromechanics to investigate the effects of cardiac resynchronization therapy on failing hearts.

Aug 6: Tools for Scientific Workflows and Visualization

Host: Michel Sanner, Ph.D., Phil Papadopoulos

Accessible Global Scale Computational Science/span>

John McGee, RENCI

Abstract The promise and lure of utility computing has been around for quite some time, however, very large scale computational science remains far away from the model of simply plugging a cord into an outlet. The complexities of heterogeneous: hardware, software stacks and environments, resource provider policies, access mechanisms, support structures, etc continue to consume too much time from scientists who need to compute at ever increasing scales. In this talk, we describe the methodology, platform infrastructure, hosted services, and support structure that we have developed to rapidly bring massive computational capabilities to scientists from many domains with a very broad range of existing IT skills and interest level. For some, this simply means quick turnaround for simulations (eg from months to weeks, or months to days), for others, this enables a whole new scale of investigation and research.

Biography John McGee is RENCI’s manager of cyberinfrastructure development, leading a team of software developers implementing solutions that advance scientific research and discovery. Mr. McGee directs RENCI's TeraGrid Science Gateway, and is the Engagement Coordinator for the Open Science Grid, helping scientists leverage OSG, a powerful cyberinfrastructure established by the high energy physics community to support global collaborations. Prior to RENCI, Mr. McGee was co-executive director of the GRIDS Center at USC-ISI as part of the NSF Middleware Initiative. He has also served in technical and managerial roles in academia and the private sector.

Visualization Environments for Multi-Scale Biomedical Modeling

Michel Sanner, Ph.D., Dept Mol Biol, TSRI

Aug 7: Grid Computing and Analysis for Multi-Scale Biomedical Applications

Host: Peter Arzberger, co-host: Phil Papadopoulos, Ph.D.

The Neuroscience Information Framework: a neuroscience-centered portal for searching and accessing diverse resources

Mary Anne Martone, Ph.D., UCSD

Abstract Although a plethora of resources (tools, databases, materials) for neuroscientists is now available on the web, finding these resources among the billions of possible web pages continues to be a challenge. The lack of discoverability is particularly acute for information contained in on-line databases, whose dynamic content is largely opaque to web search engines such as Google. Recognizing the critical need to unite scientists with tools, the NIH Blueprint consortium created the Neuroscience Information Framework (, as a means for neuroscientists to come together to spur the exchange and access of data through linking of the literature to data, building of standards for describing neuroscience and on-line community tools. This presentation will describe the architecture and rationale behind the NIF and current challenges in broad information integration in the life sciences.

Biography Dr. Maryann E. Martone is Professor-in-Residence in the Department of Neurosciences at the University of California San Diego. She also serves as Co-Director of the National Center for Microscopy and Imaging Research (NCMIR), a technology development center supported by the US National Institutes of Health, dedicated to advancing 3D imaging of cells and tissues using light and electron microscopy. Dr. Martone was trained as a neuroanatomist, with expertise in light and electron microscopy, receiving her Ph. D. in neuroscience in 1990 from UCSD. In recent years, she has focused on the development of informatics tools for light and electron microscopic data, including the creation of databases, ontologies and tools for annotation and query of neuroscience imaging data. She currently leads the Neuroscience Information Framework project, serves as the US science representative to the International Neuroinformatics Coordinating Facility, and is chair of the Neuroinformatics Committee for the Society for Neuroscience.n

Grid Computing and Analysis for Multi-Scale Biomedical Applications

Phil Papadopoulos, Ph.D., SDSC, UCSD

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