Protein Molecule Simulation on the Grid

1. G-USE in ProSim Project Protein Molecule Simulation on the Grid Tamas Kiss kisst@wmin.ac.uk Joint EGGE and EDGeS Summer School on Grid Application Support Budapest, Hungary, 3rd July 2009

2. The biological 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 biological interest Protein (receptor) Binding pocket Sugar (ligand)

4. The biological 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 an average bio-scientist • Unix command line interfaces • 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 biological interest • What does the biologist want? • Run the simulations faster • Use Grid resources • Run the simulations from a user friendly interface • Web based interface • Combine many simulation, analysis and visualisation tools into a workflow

7. 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.

8. 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)

9. 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 minimization Energy minimization Validation

10. 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

11. 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

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

13. User views • Biologist end-user • Minimal computer and g-USE skills • Only interested in running her own reserach • Import, parameterize, execute and visualise workflows only • Expert user • g-USE and computer literate biologist • Modify workflows • Design new experiments • Communicate end-user request towards IT team

14. 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

15. The ProSim visualiser

16. The ProSim visualiser

17. 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 • User is interested in her science and not in MPI, Globus or WMS.

18. 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

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