Table Of Content

RA 409. 5 N28 1993 DOT Division of Computer Research and Technology National Institutes of Health 1993 Director's feeport U.S. Department of Health and Human Services Public Health Service Bethesda, Maryland October 1993 4 y Front and back covers: Carboxymyoglobin (MbCO) surrounded by 350 watermolecules (P. J. Steinbach and B. R. Brooks, MolecularGraphicsand Simulation Section, DCRTLaboratory ofStructural Biology; seeProc. Natl Acad. Sci. USA 1993; 90:9135-39). This study simulated the molecular dynamics ofMbCO at 14 hydration levels, from to 3,830 waters/protein. On the 100-ps time scale, 350 water molecules were found to fully hydratethe protein, covering all chargedgroups and resulting in an equilibrium structure and dynamics comparable to hydration by 3,830 watermolecules. Contents Director's Preface 2 Reportofthe Associate Director, Office ofComputational Biosciences 4 Report ofthe Associate Director, Office ofComputing Resourcesand Services 7 DCRT Reorganization 11 Office ofComputational Biosciences (OCB) 16-74 Computational Bioscience and Engineering Laboratory (CBEL) 16 Laboratory of Structural Biology (LSB) 38 Physical Sciences Laboratory (PSL) 60 Office ofthe Associate Director, OCB (OAD, OCB) 70 Office ofComputing Resources and Services (OCRS) 76-139 Network Systems Branch (NSB) 76 Computing Facilities Branch (CFB) 84 Distributed Systems Branch (DSB) 94 Scientific Computing Resource Center (SCRQ 122 Customer Services Branch (CSB) 126 Information Systems Branch (ISB) 130 Office ofthe Associate Director, OCRS (OAD, OCRS) 138 Office ofthe Director (OD) 142-153 — Computational Molecular Biology Section (CMBS) 142 - Office ofInformation Resources Management (OIRM) 145 Equal Employment Opportunity Office (EEO) 147 ' W : f Office of Administrative Management (OAM) 148 "RS°F Acronyms 154 M_ I j Index 159 J bfwt?"S* *° A number ofterms used in this report are protected by copyright, trademark, or registered trademark provisions. Contact the DCRT Information Office (301-496-6203) for further information. Director's Preface The reorganization has been accomplished without an addition to ourresources in terms of budget or personnel. Thishas necessitated the The past year has been an exciting and We closing of three laboratories within the division. productive one for the Division ofComputer believe that the majority oftherestructuring is now Research and Technology. After 2 years of complete, and that the current structure of DCRT preparation - with site visits, retreats, consultation should be appropriate for several years to come. with outside advisors, and development ofa Further details about the reorganization are reorganization plan - the implementation of that givenonpp. 11-14. reorganization is now well under way. The past year Major accomplishments during the past year has seen the creation oftwo new offices: the Office include: ofComputationalBiosciences, under my direction as • reorganization of the entire division an Acting Associate Director (equivalent to the • the application of High Performance Computing Scientific Director) and an Office ofComputing and Communication (HPCC) to several important Resources and Services, headed by Emmett Ward as biomedical problems Acting Associate Director. The OCB consists oftwo CHARMM • porting ofthe programs (molecular new laboratories: theLaboratory ofStructural dynamics) and GAMESS (quantum mechanics) to Biology (Dr. V. Adrian Parsegian, Acting Chief) and the Intel® highly parallel supercomputer and to the ComputationalBioscience andEngineering Hewlett-Packard™ workstation clusters Laboratory (Dr. Robert Martino, Chief), along with • the DCRT cosponsored meetings, "High the pre-existing Physical Sciences Laboratory (Dr. Performance Computing in Chemistry" and George Weiss, Chief). The OCRS consists of two "Intelligent Systems in Molecular Biology" new branches: theNetworking Systems Branch • improved measurement of forces between (Harold Ostrow, Chief), and the Customer Services molecules Branch (Dale Spangenberg, Chief). In addition, the • improved understanding oftherole ofwater Personal Computing Branch has been restructured as surrounding proteins in allosteric transitions, protein theDistributed SystemsBranch (David Songco, conformation, computational molecular dynamics, Chief), the Computer Center Branch has been andsimulated de novo folding ofproteins restructuredas the Computing Facilities Branch • improved prediction ofprotein secondary structure (Perry Plexico, Acting Chief), and the Data • classificationofprotein structures Management Branch has become the Information • a new model for assembly ofclathrin-coated Systems Branch (Marvin Katz, Acting Chief). Ray vesicles Danner heads the Statistical Support Staff, and an • expansion ofNTHnet to include 224 local area Architectural Management StaffandaFunding networks (LANs) with 105 on-campusLANs Management Staffhave been created. These connected via high-speed fiber backbone restructurings are more than a change ofname ora • provision ofnew information services over the "facelift"; these are real changes in mission, network, including MEDLINE, CurrentContents®, orientation, strategy, tactics, personnel, physical REFERENCE UPDATE®, Gopher™, and multiple location and resources. In addition to the OCB and genetic databases such as GenBank OCRS, we have created a DCRT Office of • a new set ofsoftware tools for medical and Information Resources Management, headed by laboratory image processing (Multimodality Arthur Schultz; Frances Halverson has been named Research Image Processing System (MRIPS), with AssistantDirector for Programs; and the Capacity LDRR (Nffl/OD), NCRR and the ICDs) Management Staffcontinues to play its important • a successful first year ofoperation for the function. Scientific Computing Resource Center presentation ofthe 1992 Best of Open Systems • support forNTHOfficeofthe Directoradminist- Solutions (BOSS) Award for Innovation in rative systems Hardware, Software and Networking Approaches to • reconfiguration of the Central Computer Facility DCRT's Advanced Laboratory Workstation (ALW) • substantial rate reductions and rebates for Project mainframe services 1 new courses on molecular modeling and • improved liaison with the user community experimental design • planning and initial studies for reprocurementof 1 support for large-scale sequencing efforts (with the mainframe, and appointment ofa "trailboss" to NINDS andNCI) manage the reprocurement and coordination with the evaluation of client/server technologies multiple Federal agencies ' ' majorefforts on such information resources • upgrade of the speed of telecommunications management activities as disaster recovery, data interfaces security, new procurement mechanisms and site • new equal employment opportunity initiatives licensing • adoption ofa high school, to encourage students to 1 advances in hardware and technology (e.g., enter careers in computing and biomedical workstation clusters) research. ' participation in NTH-wide activities, including Beyond these present accomplishments lies training, lectures, seminars, andjournal clubs; the future of DCRT, and the scientific and organizational consults (e.g., NCHGR, NINR); and administrative computing advances needed for NIH the development ofa new User Resource Centerat to move into the twenty-firstcentury. Executive Plaza (with the Division ofPersonnel Management) David Rodbard, M.D. DCRT Director, Office of Computational Structural Biology. For practical purposes, every application which has been attempted has been Biosciences successful. In each case, we are seeing speedups in processing time ofSO- to 100-fold, close to the To exploit the power ofthe division's parallel theoretical maximum, making it possible to attempt scalable supercomputer (the Intel® IPSC i860 128- projects which otherwise would have been node machine), the Computational Bioscience and impossible or impractical. This is the major effort at Engineering Laboratory has made significant NIH in the area ofHigh Performance Computing progress in the adaptation and parallelization of Systems, part of the High Performance Computing, several computer codes for important biomedical Communications, and Information Technology applications. Applications include: initiative of the Federal Coordinating Council for • image processing Science, Engineering, and Technology of the • computational chemistry Committee on Physical, Mathematical, and • quantum chemistry Engineering Sciences. In this regard, we cosponsored • genetic database searching a meeting on "High Performance Computing in • protein structure determination Chemistry" jointly with the Pacific Northwest • protein structure prediction Laboratories ofthe DepartmentofEnergy. Dr. Robert • multiple sequence alignment. Martino and coworkers were also important A briefsummary is shown in Table 1. This work has contributors to a meeting sponsored by NASA on involved collaborations with investigators in NIAMS, high performance computing, and the division was a NIDDK,andNCI,and in DCRTsLaboratoryof cosponsor ofa meeting on Intelligent Systems in Table 1. DCRT High Performance Biomedical Computing Program Representative Collaborative Research Activities BiomedicalApplication Collaborator Organization Structural Biology Electron Microscopy A. C. Steven LSBR, NIAMS NMR Spectroscopy A.Bax LCB,NTDDK x-Ray Crystallography C. G.Hyde LSBR, NIAMS Protein Folding Prediction B.Lee LMB.NCI Medical Image Processing PET Reconstruction R. E. Carson NMD, CC Functional Neurological J. V.Haxby LPP.NIMH Analysis T.Zeffiro LN.NIA Computational Chemistry Quantum Chemistry B.Hardy DBB, CBER Molecular Dynamics W. A.Eaton LCP.NIDDK Simulations E.Henry LCP.NIDDK Genetic Linkage Analysis E.S.Gershon CNB.NIMH Radiation Treatment Planning J. van de Geijn DCT.NCI Molecular Biology immediately preceding the Research of NIAMS, he has been able to make national meetings of the American Association for tentative identification ofthe role ofeach of the Artificial Intelligence. Our Intel® parallel super- seven proteins comprising the capsid The studies computer is now being utilized at capacity, and it is have been facilitated by the ability to selectively imperative that we obtain an appropriate follow-on extract one or another ofthe proteins, leaving a hole machine with additional capacity to keep us current where it once was, and by the use ofmonoclonal Figure 1. The Computational Bioscience and Engineering Laboratory, DCRT, in collaboration with the Laboratory ofStructural Biology, NIAMS and the University of Virginia, Charlottesville, is involved in the 3D reconstruction ofviruses. Shown are surface-shaded representations ofherpes simplex virus (HSV) type 1. The HSV-1 capsid has a diameterof~125nm, and is constructed according to icosahedral symmetry. The left image is an empty capsid as viewed down the five-foldaxis ofsymmetry. The locationsofthe various capsid proteins have been investigated by biochemical depletion experiments. Treatment of capsids with the denaturant, guanidinium hydrochloride, extracts certain capsid components while preserving its icosahedral geometry, as shown in the right ima—ge. The pentons are removed quantitatively; cf. the empty vertex sites. Also removed are some ofthe triplexes nodules thatoccupy the local sites ofthree-fold symmetry. (Electron microscopy, image reconstruction,and computergraphics: B. L. Trus (DCRTand NIAMS) andF. P. Booy, J. F. Conway, and A. C. Steven (NIAMS); virus preparation, biochemistry: J. C. Brown and W. W. Newcomb (University of Virginia); reconstruction software: T. S. Baker (PurdueUniversity) and C. A. Johnson and N. I. Weisenfeld (DCRT). Computationally intensive steps were performed on the DCRT Intel iPSC/860 parallel supercomputer. in terms ofthe rapidly evolving technology and antibodies selective for each ofthe proteins (Figure increasing applications. 1). The investigations are contributing to an Dr. Benes Trus, Chiefofthe Image Processing improved understanding ofthe structure (and hence Section, CBEL, as made considerable progress in his function) ofthe various parts ofthe virus capsid (e.g., studies of the structure of the herpes simplex type 1 "pentons," "hexons," VP1, VP2, VP7). This should virus. Using computeranalysis ofcryoelectron facilitate studies of the mechanisms of infectivity micrographs obtained by his colleagues and and replication ofthe virus, and lead to the collaborators in the Laboratory ofStructural Biology development of pharmacological agents to interfere with the life cycle ofthis virus. The studies should rigorous statistical method helps to make sense of generalize to a variety of other viruses, both in the the conflicting claims in the literature, and show that herpes family andothers. Dr. Trus' work also all methods are reaching an upper plateau ofabout illustrates the importance of high performance (read, 62% accuracy. Further improvement will require "parallel scalable") computing in facilitating and additional information, e.g., prior classification of accelerating biomedical research. proteins into various categories. In theLaboratory ofStructuralBiology, Dr. Richard Feldmann is exploring a variety of Sergey Leilrin has measured the forces involved in new and novel approaches to analysis of the the packing ofcollagen triple helices, as a function "topology" ofde novoprotein folding. of temperature, pH, ionic strength and ionic milieu, Dr. George Weiss, ChiefofthePhysical using the Tarsegian" method to apply osmotic force Sciences Laboratory, has completed a major and x-ray diffraction to measure intermolecular monograph entitled "Introduction to Crystallographic distance. Surprisingly, hydration forces are a major Statistics" and edited a volume entitled "Contempo- determinant ofthese forces, as in the case ofDNA- rary Problems in Statistical Physics." He has DNA, DNA-protein, and lipid-lipid interactions. continued work with Dr. Uri Shmueli (Visiting These results will now be examined in a variety of Scientist) on the theory ofcrystallography of small disease conditions involving abnormal collagen molecules. structures. Dr. Leikin and Dr. Parsegian continue a Dr. Ralph Nossal and Dr. AlbertJin (Visiting number ofimportant collaborations with researchers Fellow) have developed a new and novel theory for inNIDDKandNIAMS. the mechanism ofassembly ofclathrin triskelions to Dr. Bernard Brooks (Chief, Molecular form coated vesicles. This model appears to solve Graphics and Simulation Section) and Visiting several serious geometrical and physical problems, Fellow Dr. Milan Hodoscek have adapted the and is now ready for experimental evaluation. CHARMM program for molecular dynamics to the In addition to our seminar series, DCRT Intel® parallel computer, and in turn, to a cluster of sponsors ajournal club devoted to protein folding, workstations, providing economical and cost- and another devoted to biomedical applications of effective methods for long-term simulations. Dr. Peter artificial neural nets. Steinbach has examined the role of hydration in Finally, mention should be made ofDCRT's modulating the structure ofmyoglobin by systemati- Image Technology Program, headed by the Clinical cally varying the degree ofhydration from zero to a Center's Dr. Stephen Bacharach under ajoint high level (see figures on frontand back covers of DCRT/CC appointment This program links DCRT this report). Dr. David Chatfield is making significant staff to collaborators in the CC and several ICDs progress in the modeling of alternative reaction with the goal ofdeveloping improved methods for in mechanisms for HTV protease, using a combined vivo image analysis and processing. Current projects quantum mechanical/molecular mechanics in which DCRT is involved include: (QM/MM) approach. • 3D alignment ofpositron emission tomography Dr. Peter Munson (Chief, Analytical (PET) transmission scans Biostatistics Section), Dr. Raul Porrelli and Dr. • automatic tracking of magnetic resonance imaging Valentina di Francesco (Visiting Fellows) have used (MRT) "Tag" grids a variety of sophisticated statistical methods to • maximum likelihood estimation of regional predict the secondary structure ofproteins on the radioactivity concentration basis ofprimary sequence. By use ofgeneralized • computer-guided surgery. cross-validation, they have been able to compare the performance ofdifferent methods which explicitly or David Rodbard, MJ>. implicitly use different numbers ofparameters. This Acting Associate Director, OCB Office of Computing in devising and implementing workable strategies for Resources and Services migrating NIH computing to open systems. •DistributedSystemsBranch (DSB). Addresses the increasing demand for service, support and guidance DCRT finalized a Strategic Plan and in the selection and effective use ofpersonal reorganized to align ourselves with that plan during computers, workstations, local area networks, and FY93. Theplan and thus the new organization associated automation technology; provides advice address three major programs: Research and and assistance on issues relating to multiplatform Development, Computer Resources Infrastructure, client/server and database support; and provides and Direct Computing Services and Support The primary planning and support for the Scientific Director, NIH approved the establishmentoftwo new Computing Resource Center (SCRQ. offices, one dealing with services, support, • Customer ServicesBranch (CSB). Serves as the infrastructure and facilities (Office of Computing primary user contact for information, support and Resources and Services (OCRS)), and the other with training within DCRT; manages and facilitates the research and development for the computational resolution ofuser problems with the appropriate staff biosciences (Office of Computational Biosciences in DCRT; and, in general, acts as the user advocate (OCB)). Key elements of the OCRS organization within the DCRT. include: •Information SystemsBranch (ISB). Provides • creation ofa central point ofcontact for all continued support for the NIH Administrative Data services and support in the division Base (ADB), the Central Accounting System (CAS), • a central focus for campus-wide networking and the Clinical Information Utility (CIU); serves as • consultation and support forevolving distributed an NTH resource for database design, systems systems technology analysis and programming; and plays the lead role in • consolidated operation, maintenance and support of evaluating, selecting and supporting NIH client and all DCRT hardware and softwareplatforms for local workstation and serverdatabase products. shared and enterprise use In addition to the branches, a Statistical • creation ofa core mechanism for identifying and Support Staffhas been established to provide direct evaluating opportunities to make the transition to advice, assistance and support to biostatisticians and open systems environments. othersat theNIH whoeitherare using orare The functional definition ofthe new branches ofthe planning to use statistical-software on central and OCRS and the reallocation ofresources is well under distributed platforms. Representatives from each of way at this writing. A quick listofthe branches and the branches also participate on the Architectural their primary functions follows: Management Staff and the Funding Management •Network SystemsBranch (NSB). Designs, develops Staff. The objectives ofthese two staffgroups are, and supports all network facilities and services respectively, to foster collaboration related to DCRT- related to NIHnet, the NTH-wide backbone wide architectural planning, and to identify and infrastructure; fosters computational interoperability; develop mechanisms for new DCRT cost recovery and promotes the development ofstate-of-the-art alternatives. networking technology. The Customer Services Branch is already • Computing FacilitiesBranch (CFB). Develops, preparing to assume its pivotal role in the operates, maintains and supports central hardware reorganization. A client/server facility is being and software platforms for shared and enterprise use; developed to supportproblem tracking and resolution evaluates, installs and maintains central servers, across the OCRS; plans for a new centralized gateways and database management facilities that training program are in place. Consolidation ofuser support client/server computing; and takes the lead services with a central point of contact and a single phone number for assistance will help to speed the the commercial Inherit™ system. He has recently NIH researcheroradministratorto theproper DCRT beenjoined in this effort by Dr. Mark Millerfrom resource for his/her information and support NCI, and is providing major support to researchers in requirements. NINDS,NCIandNCHGR. Even as plans to move supportfor open In addition, DSB's Dr. James Malley has systems to the CFB were in gestation, the Federal completed a monograph on "Quantum Statistical Computer Conference bestowed an honor upon the Inference" which is now in press as a series of staffofthe AdvancedLaboratory Workstation journal articles. (ALW) Project, formerly part ofthe Computer The Statistical Support Staff sponsored a Systems Laboratory. The ALW system received the Mathematical and Statistical Software Fair at NIH 1992 Best ofOpen Systems Solutions (BOSS) Award during December 1992. This was the firstofits kind, forInnovation in Hardware, Software andNetworking and it introduced NIH mathematicians and Approaches. statisticians to multiplatform mathematical and Higher communications speeds and enhanced statistical packages. A questionnaire was distributed error correction for the CFB's interactive services - among the attendees and important data were in the form ofnew communication controllers and compiled on software packages ofinterest to the NTH new state-of-the-art modems - will open up community. capabilities and functions such as large file transfers, Interest in the ADB Information System which have not been previously viable. (ADBIS) was such that several formal demonstra- For the 25th consecutive year, cost savings tions were presented in the Lipsett Amphitheater. were passed on to users of the computer center in the The ADBIS represents the fruition ofa collaborative form of significant rate reductions, rebates, and effort among ISB staffand over 70 representatives discounts ranging from 21% to 28%. from all ofthe ICDs. This effortis being coordinated The Scientific Computing Resource Center by Mr. Mark KochevarofNCI who is serving as (SCRC), now located in the DSB, was piloted in Chairman ofthis ADB Steering Subcommittee. The May 1992 and is now flying strongly, especially with ADBIS is an online system which provides standard the opening of its Image Technology Center in July query facilities that are specifically designed to 1993. The center has been particularly popular for respond to the requirements developed by the molecular modeling, sequence analysis, graphics and subcommittee. statistics. - During the fiscal year, the increased speed of DSB and other branches have collaborated in Fiber Distributed Data Interface (FDDI) was beta-testing new products such as Windows™ NT extended to an additional 110 local area networks and the various Lotus 1-2-3 releases. This positions (LANs) in 10buildings on the NTH campus. FDDI DCRT to influence product enhancements that will operates at 100 megabits per second and portends the meet the particular requirements of the NIH ability to accommodate transfer oflarge files for community. image processing, full-motion video, genome DSB's Dr. Dale Graham has developed new mapping and other research applications that require courses and training manuals to assist in the use of massive data transfer at high speed. Currently, there GenBank, other databases, MacVector™, GCG and are about 250 LANs on the NIHnet, which serves other sequence analysis programs. John Powell sites on and offthe campus. This number will continues to play a major role in the automation of probably grow toaround 330 during the coming year, laboratories performing large-scale sequencing. His and NSB plans to provide the most advanced, expertise includes hardware, software, networking appropriate and latest supportable technology for and databases, engineering, and application of new each site. technologies such as the "fast data finder" chip and