The background to the Comb-e-Chem e-Science pilot project funded under the UK-Science Programme is presented and the areas being addresses within chemistry and more specifically combinatorial chemistry are discussed. The ways in which the ideas underlying the application of computer technology can improve the production, analysis and dissemination of chemical information and knowledge in a collaborative environment are discussed

Frey, Jeremy G.

English

Southampton (e-Prints Soton)

CombeChem: An e-Science Research ProjectJeremy G. FreyDepartment of Chemistry, University of SouthamptonSouthampton , S017 1BJ, UKEmail: j.g.frey@soton.ac.uk Tel: 023 8059 3209 www.combechem.orgIntroduction: The e-Science programme.In November 2000 the Director General of Research Councils, Dr John Taylor, announced £98M funding for anew UK e-Science programme.  e-Science refers to the large scale science that will increasingly be carried outthrough distributed global collaborations enabled by the Internet.  While the World Wide Web gave us access toinformation on Web pages Internet a much more powerful infrastructure is needed to support e-Science.  Thisinfrastructure is the GRID.  Besides information stored in Web pages, the Grid will provide scientists with easyaccess to expensive remote facilities, to computing resources, distributed databases and enable collaborationwithout regard to geography (well within the limits of the speed of light).All the UK research councils were allocated funding under this programme and research relevant to Chemistryand the general pharmaceuticals area is being funded by the EPSRC, BBRC.  The environmental concerns of theNERC look interesting in this context as well.  The funding strengthens and significantly extends the work beingundertaken by the UK Interdisciplinary Research Centres (IRC) such as the “Advanced KnowledgeTechnologies (AKT)” project the EQUATOR (project and the Medical Imaging and Signals project whichenables “distributed medicine”.  The e-Science Core Programme set up a national infrastructure to support e-Science/Grid activities including a National e-Science Centre at Edinburgh (www.nesc.ac.uk), Regional Centresand Grid Support and Grid Network teams based round the CCLRC.  There are strong links to EU projects inthe e-Science and Grid Area.  An aim of the UK e-Science research is as a bridge between the US viewpoint andthe European view.The UK Computer Science research base brings significant abilities and understanding in the arena of“Knowledge Engineering” to the vision of readily available computational resources.  This plays the UKstrengths formed via JISC supported activities for library resources such as UKOLN and DNER.  The“Knowledge Engineering” aspects of our projects is particularly important as the availability of hugecomputational and network resources is not sufficient for achieve research - it is not always what resources youhave but how you use them that is important.The Comb-e-Chem ProjectChemistry has always made extensive use of the developing computing and information technologies and beenan avid consumer of available computing power.  Chemical uses of the technology include activities such asmodelling, simulation and chemical structure interpretational; activities conveniently summarised ascomputational chemistry.  New procedures in chemical synthesis and characterisation, particularly in the arenaof parallel and combinatorial methodologies, have generated ever-increasing demands on both ComputationalChemistry and Computer Technology.  However, significantly the way in which networked services are beingconceived to assist collaborative research pushes well beyond the traditional computational chemistryprogrammes, towards the basic issue of handling Chemical information and knowledge.  The rate at which newchemical data can now be generated in Combinatorial and Parallel synthesis and screening processes means thatthe data can only realistically be handled efficiently by increased automation of the data analysis as well as theexperimentation and collection.XML ExchangesIn starting to set up the Comb-e-Chem project we realised that it is essential to develop mechanisms forexchanging information.  This is of course a common feature of all the e-science projects, but the visual aspectsof chemistry do lead to some extra difficulties.  Many chemists have been attracted to the graphical interfacesavailable on computers.  The drag-and-drop, point-and-shoot techniques are easy and intuitive to use but presentmuch more of a problem to automate than the simple command line program interface.  Fortunately these twostreams of ideas are not impossible to integrate, but it does require a fundamental rethink on how to implementthe distributed systems while still retaining (or perhaps providing) the usability required by a bench chemist.One way in which we will ensure that the output of one machine or program can be fed in to the next program inthe sequence is to ensure that all the output is wrapped with appropriate XML.  In this we have some advantagesas Chemists, Chemical Mark-up Language (cML) was one of the first XML systems to be developed by PeterMurray-Rust1.Figure 1:Showing the use of XML wrappers tofacilitate the interaction between twotypical chemistry calculationprograms.  .  The XML (perhaps cMLand other schema’s) ensures that atransparent, flexible, reusable andflexible workflow can be implemented.The resulting workflow system canthen be applied to all the elements of acombinatorial library automatically.Figure 1 illustrates this for a common situation where information needs to be passed between a Quantummechanical calculation that has evaluated molecular properties2 and a simulation programme to calculate theproperties of a bulk system or interface.  It equally applies to the exchange between equipment and analysis.  Atypical chemical application would involve for example a search of structure databases for the details of smallmolecules, followed by a simulation of the molecular properties of this molecule, then matching these results byfurther calculations against a protein binding target selected from the protein database and finally visualisationof the resulting matches.  Currently the transfer of data between the programs is accomplished by a combinationof macros and Perl scripts each crafted for an individual case with little opportunity for intelligent reuse ofscripts.  Proper analysis of this process and the implementation of a workflow will enable much betterautomation of the whole research process3.Figure 1 illustrates another issue; more information may be required by the second program than is available asoutput from the first.  Extra knowledge (often experience) needs to be added.  The Quantum program providesfor example a molecular structure but the simulation program requires a force field (describing the interactionsbetween molecules).  This could be simply a choice of one of the standard force fields available in the packages(but a choice never-the-less that must be made) or may be derived from additional calculations from the QMresults.  This is where the interaction between the “Agent” and the workflow appears4,5.Virtual DataA Combinatorial Library could be thought of as a “Library Collection” with the material itself and all theinformation on that material all ideally cross-referenced.  If information is requested from a library then it can beprovided if it is held in the collection, if not a search can be made to locate and deliver it from elsewhere.  Forthe chemical information searches spilling out to a from a wide variety of databases are common but the powerof the Grid based approach to the handling of the combinatorial data is that we can go further than this “static”approach.Figure 2 VirtualDataAn example of virtualdata interactions inthe context of acombinatorial family.The calculations of anunknown material canbe calibrated againstknown members of thelibrary.Gaussian ab initioprogramXML wrapper XML wrapperSimulationprogramInterface InterfacePersonal AgentPersonal AgentprogramXML wrapper XML wrapper XML wrapper XML wrapperInterfacePersonal AgentPersonal AgentXML wrapperGaussian ab initioprogramXML wrapper XML wrapperSimulationprogramInterface InterfacePersonal AgentPersonal AgentprogramXML wrapper XML wrapper XML wrapper XML wrapperInterfacePersonal AgentPersonal AgentXML wrapper Request??R1R2XR3R4 R1R2XR3R4Simulate bulk structure from molecular propertiesQuantum Mechanical calculation of molecular propertiesCombinatorial Library  DatabaseValidate against other members of the family????R1R2XR3R4 R1R2XR3R4Simulate bulk structure from Combinatorial Library  Databasethe family??Request??R1R2XR3R4 R1R2XR3R4Simulate bulk structure from molecular propertiesQuantum Mechanical calculation of molecular propertiesCombinatorial Library  DatabaseValidate against other members of the family????R1R2XR3R4 R1R2XR3R4Simulate bulk structure from Combinatorial Library  Databasethe family?? The combination of the high throughput laboratory equipment and the resulting information, together with thecalculation resources of the Grid allows for a much more interesting “library network” to be created.  As shownin Figure 2 an appropriate model can calculate the requested data.  These models are themselves validated bycomparison with the measured properties of the actual physical members of the library.  Depending on time orresource constraints different types of model, or different levels of implementation of a model can be chosen,ranging from resource hungry high level quantum mechanical calculation, through extensive simulations, to anempirically based approached; we thus have in effect a virtual entry in the database.  In the limit this process hasa close connection with the ideas of virtual screening of combinatorial libraries.As in our model the Grid extends down in to the laboratory this virtual data idea can be extended to not onlycalculations but also to new experimental data acquisition or even automated synthesis.  That is the direction ofthe synthesis or analysis in the automated laboratory would be controlled via a database request.  The delegatedactivation of computational and physical resources has many implications for security, accountability andaccounting.Statistical ModelsThe presence of a large amount of related data such as that obtained from the analysis of a combinatorial librarysuggests that it would be productive to build simplified statistical models to predict complex properties rapidly.A few extensive detailed calculations on some members of the library will be used to define the statisticalapproach, building models using, for example, appropriate regression algorithms or neural nets or geneticalgorithms, that can then be applied rapidly to the very large datasets.The rapid acquisition of new information means that the very processing of data via these statistical models andthe resulting comparisons that will be made generate new information that can be used to modify the statisticalmodels.  The speed with which can envisage the design – experiment-analysis-model building-modify-designcycles means that it is more appropriate to consider the new data flowing through the workflow as potentiallymodifying that workflow.  The automated analysis becomes an example of a self modifying network bring usvery close to the frontiers of Computer Science Research.Figure 3 The e-Publication chain for multimedia Chemistry InformationPublication@SourceChemistry is a multimedia subject – 3D structures are key to our understanding of the way in which moleculesinteract with each other.  The historic presentation of results originally as text and then on a flat sheet of paper isto limiting for current research.  3D projectors are now available, dynamic images and movies are now requiredto portray adequately the chemist’s view of the molecular world.  This dramatically changes expectations ofwhat a journal will provide and what is meant by “publication.  Chemistry is becoming an information science6,,but exactly what information should be published?  And by whom? The traditional summary of the researchwith all the important details will continue to provide a productive means of dissemination of the chemicalideas.  The databases and journal papers link to reference data provided by the authors and probably held at thejournal site or a subject specific authority.  Further links back to the original data take you to the author’slaboratory records.  The extent type of access available to such data will be dependent on the authors as will bethe responsibility of archiving these data.  There is thus inevitably a growing partnership between the traditionalauthorities in publication and the people behind the source of the published information, in the actualpublication process.Journal JournalMaterialsDatabaseMultimediaLaboratory DataPaper“Full” record Journal Journal Journal JournalMaterials Reference MaterialsDatabase DatabaseMultimedia MultimediaLaboratory Data Analyzed DataPaper Paper“Full” Laboratory record “Raw Data”Establish Authenticity?Path back to original materialsEstablish Authenticity? Establish Authenticity?This may be the originating labsPath back to original materials Path back to original materials – Audit TrailLong term storage by originatorsMay not be able to rely on traditional authoritiesPaper or reference databaseAbility to recalculate dataJournal JournalMaterialsDatabaseMultimediaLaboratory DataPaper“Full” record Journal Journal Journal JournalMaterials Reference MaterialsDatabase DatabaseMultimedia MultimediaLaboratory Data Analyzed DataPaper Paper“Full” Laboratory record “Raw Data”Journal Journal Journal JournalMaterials MaterialsDatabase DatabaseMultimedia MultimediaLaboratory Data Laboratory DataPaper Paper“Full” record Journal Journal Journal JournalMaterials Reference MaterialsDatabase DatabaseMultimedia MultimediaLaboratory Data Analyzed DataPaper Paper“Full” Laboratory record “Raw Data”Establish Authenticity?Path back to original materialsEstablish Authenticity? Establish Authenticity?This may be the originating labsPath back to original materials Path back to original materials – Audit TrailLong term storage by originatorsMay not be able to rely on traditional authoritiesPaper or reference databaseAbility to recalculate dataEstablish Authenticity? Establish Authenticity?Path back to original materials Path back to original materialsEstablish Authenticity? Establish Authenticity?This may be the originating labsPath back to original materials Path back to original materials – Audit TrailLong term storage by originatorsMay not be able to rely on traditional authoritiesPaper or reference databaseAbility to recalculate dataWe seek to formalise this process by extending the nature of publication to include links back to informationheld in the originating laboratories.  In principle this should lead right back to the original records (spectra,laboratory notebooks) which will give much greater use and re-use of the original data.  The consequentchecking of the data and application of different approaches to the analysis will also be beneficial.Other e-Science ProjectsCombeChem has strong links with two of the other e-Science projects Reality Grid and MyGrid.  RealityGrid isa collaboration whose aim is to grid-enable modelling and simulation of condensed matter structures at themeso- and nanoscale levels, and the discovery of novel materials.  MyGrid aims to design, develop anddemonstrate higher level functionalities over an existing Grid infrastructure that support scientists in making useof complex distributed resources producing a virtual laboratory workbench that will serve the life sciencescommunity and bioinformatics community.ConclusionsThe Grid infrastructure when fully developed will enable the Chemist to sit at the centre of a virtual world withsimple, rapid access to a wide range of physical, computational and informatics resources.  The implementationof automatic knowledge handling right from the inception of an experiment, through all stages of analysis anduse of the information generated, will enable the single human mind to work collaboratively with others to keeppace with the exponentially growing quantities of chemical information generated by combinatorial techniquestaking place in “dark” high throughput laboratories.  Without such techniques we run the very real risk ofgenerating even more information that is effectively hidden from the very people who should be using it.AcknowledgementsIn addition to myself the main investigators of the Comb-e-Chem project are M.B. Hursthouse, D.C. De Roure,J.W.Essex, S.M. Lewis, A.H. Welsh, M. Surridge.  Together with the Universities of Southampton and Bristolseveral companies and organisations are involved in the project in particular IBM and CCDC have madesignificant contributions to the early stage of the project.References                                                   1 Chemical Markup Language, P. Murray-Rust World Wide Web Journal, 1997, pp135-1472 The Past present and Future of Quantum Chemistry, T. D. Crawford, S. S. Wesolowski, E.F. Valeev, R.A.King, M.L. Leininger and H.F. Schaefer III, Chapter 13 (pages 219 – 246) in Chemistry for the 21st Century, E.Keinan and I. Schechter Eds. Wiley-VCH, 2001, Weinheim, ISBN 2-527-30235-2.3 Leymann, F. and D. Roller. "Workflow-based Applications", IBM Systems Journal, 36 (1997) 1, pp. 102-123.4 M. Wooldridge and N.R. Jennings: Intelligent Agents: Theory and Practice, The Knowledge EngineeringReview, 10 (2), pp. 115-152, 1995.5 N. R. Jennings (2001) "An agent-based approach for building complex software systems" Comms. of theACM, 44 (4) 35-41.6 “Some Reflections on Chemistry”, J.M. Lehn, Chapter 1 (page 1-7), in Chemistry for the 21st Century, E.Keinan and I. Schechter Eds. Wiley-VCH, 2001, Weinheim, ISBN 2-527-30235-2.

1-7), in Chemistry for the 21 st Century, E. Keinan and I. Schechter Eds.

An agent-based approach for building complex software systems&quot;

Intelligent Agents: Theory and Practice,

Murray-Rust World Wide Web Journal,

The Past present and Future of Quantum

Workflow-based Applications&quot;,

Comb-e-Chem: an e-science research project

http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.131.9294

Comb-e-Chem: an e-science research project

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