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Parameter Sweep Workflows for Modelling Carbohydrate Recognition

ProSim Project. Parameter Sweep Workflows for Modelling Carbohydrate Recognition. Tamas Kiss, Gabor Terstyanszky , Noam Weingarten Pamela Greenwell, Hans Heindl AHM’09 Oxford, UK, 07-09 December 2009. The research interest. The motivation:

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Parameter Sweep Workflows for Modelling Carbohydrate Recognition

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  1. ProSim Project Parameter Sweep Workflows for Modelling Carbohydrate Recognition Tamas Kiss, Gabor Terstyanszky, Noam WeingartenPamela Greenwell, Hans Heindl AHM’09 Oxford, UK, 07-09 December 2009

  2. The research interest • The motivation: • Understanding how sugars interact with their protein partners may lead to development of new treatment methods for many diseases. • The obstacle: • Investigation of the binding of proteins to sugars in “wet laboratory” (in vitro) experiments is expensive and time consuming • Expensive substrates • Sophisticated machinery • The solution: • Use “in silico” tools (computer simulation) to select best binding candidates • In vitro work only on selected candidates

  3. The research task Protein (receptor) Binding pocket Sugar (ligand)

  4. The research interest • Advantages of in silico methods: • Better focusing wet laboratory resources: • Better planning of experiments by selecting best molecules to investigate in vitro • Reduced time and cost • Increased number of molecules screened • Problems of in silico experiments: • Time consuming • Weeks or months on a single computer • Simulation tools are too complex for bio-scientists • Unix command line interfaces + software packages (Amber, GROMACS) • Bio-molecular simulation tools are not widely tested and validated • Are the results really useful and accurate?

  5. What can we gain via the simulation? • Validation and refinement of in-silico modelling tools • Filter potential scenarios for wet lab experiments

  6. The researcher’s interest • What does the researcher want? • Run the simulations faster • Use compute resources – National Grid Service (NGS) • Run the simulations • Using seamless access to compute resources web based interface • Combining many simulation, analysis and visualisation tools • workflows • Running multiple docking experiments to investigate different protein and sugar combinations parameter study

  7. Westminster Grid Application Support Service (W-GRASS)

  8. Application Ported by W-GRASS • Bio- and Life Science • Molecular Dynamics Simulation using CHARMm • Patient Readmission Analysis with R • - GAMESS-UK - ab initio molecular electronic structure program • MultiBayes - program for analysing DNA sequences of genes • ProSim - Modelling Protein Carbohydrate Recognition in-silico – application • In silicoModelling Using AutoDock • Engineering • - DASP - Digital Alias-free Signal Processing • Extraction of X-RAY Diffraction Profiles • Cellular Automata-Based Laser Dynamics • Multi-media • Rendering portal - Grid-based on-line rendering service • Physics • VisIVO – Visualisation Interface to the Virtual Observatory

  9. ProSim – Protein Molecule Simulation on the Grid • Funded by the JISC- ENGAGE program • Engaging Research with e-Infrastructure • promote the greater engagement of academic researchers in the UK with the UK's e-Infrastructure • Prosim objectives: • define user requirements and user scenarios of protein molecule simulation • Identify, test and select software packages for protein molecule simulation • automate the protein molecule simulation creating workflowsand parameter studysupport. • develop application specific graphical user interfaces • run protein molecule simulation on the UK National Grid Service and make it available for the bioscience research community.

  10. The User Scenario PDB file 1 (Receptor) PDB file 2 (Ligand) Phase 2 Check (Molprobity) Phase 3 Energy Minimization (Gromacs) Perform docking (AutoDock) Validate (Molprobity) Phase 1 Phase 4 Molecular Dynamics (Gromacs)

  11. The User Scenario in detail phase 1 – selection and preparation of receptor phase 2 – selection and preparation of ligand Public repository Local database User provided Built using SMILES Public repository Local database User provided Preparation and standardisation Solvation and charge neutralization Solvation Energy minimisation Energy minimisation Validation

  12. The User Scenario phase 4 – refining the ligand-receptor molecule (performed on 10 best results of the AutoDock simulation) phase 3 – docking ligand to receptor Solvation of the ligand-receptor structure Prepare docking: docking parameters and grid-space - AutoGrid Energy minimisation – GROMACS Docking and selection of best results according to total energy AutoDock 10 AutoDock executions, 100 genetic algorithm runs each Molecular dynamics GROMACS MPI version Molecule trajectory data analysis

  13. The Workflow in g-USE • a combination of GEMLCA and standard g-USE jobs • Executed on 5 different sites of the UK NGS • Parameter sweeps in phases 3 and 4

  14. Running simulations Set input parameters Upload input files Select executor sites Follow execution progress Typical execution time: 24 hours

  15. User views • Researchers (or End-User) • Minimal computer, Grid and portal skills • Only interested in running their own research • Import, parameterize, execute and visualise workflows • Application Developers (and/or Expert Users) • Computer literate researcher or software engineer • Define user scenarios and design new experiments • Create, test and deploy and modify workflows • Communicate with end-users and consider their requirements

  16. The ProSim visualiser • Visualisation in a newly developed portlet • Allows visualisation of receptor, ligand and docked molecules at any phase during and after simulation (if the necessary files have already been generated) • Allows to visualise and compare two molecules at a time. • Energy, pressure, temperature and other important statistics statistics are also displayed. • Using the KiNG ((Kinemage, Next Generation) visualisation tool

  17. The ProSim visualiser

  18. The ProSim visualiser

  19. Lessons learned • Communication between scientists and Grid experts is extremely difficult • More than 50% of total time spent for the project is for communication and describing/understanding user requests/requirements • Novice Grid users require totally transparent access to Grid resources • Users interested in their research and not in Globus, MPI or WMS.

  20. Future plans • Make workflow more flexible to accommodate numerous different user scenarios • Investigate further scenarios such as virtual screening of many ligands to one selected receptor

  21. Thank you for your attention!Any questions? https://engage.cpc.wmin.ac.uk kisst@wmin.ac.uk

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