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Folding@home and SWISS-MODEL

Folding@home and SWISS-MODEL. Taru Tukiainen ja Sini Sipponen S-114.2500 13.12.2006. Two Different Approaches to Protein Structure Modeling. Outline. Introduction to protein modelling Modelling the folding process with Folding@home Comparative modelling with SWISS-MODEL. Introduction.

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Folding@home and SWISS-MODEL

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  1. Folding@home and SWISS-MODEL Taru Tukiainen ja Sini Sipponen S-114.2500 13.12.2006 Two Different Approaches to Protein Structure Modeling

  2. Outline • Introduction to protein modelling • Modelling the folding process with Folding@home • Comparative modelling with SWISS-MODEL

  3. Introduction • Proteins are formed from a sequence of amino acids • Primary structure = polypeptide chain • Secondary structure • alpha helix • beta sheet • Tertiary structure is 3D • Quaternary structure is comprised of several tertiary structures • Native state is the functional form

  4. Hydrophobic effect on Folding • Important force affecting the forming of the tertiary structure • Many residues of amino acids are hydrophobic • leads to the formation of a hydrophobic core • After folding, entropy of protein decreases, but the entropy of system decreases • Entropy promotes the folding process

  5. Misfolding • Prions are result of faulty folding • Little known about how they form • Can convert normal protein molecules to prions

  6. The Problems • Impossible to predict 3D structures from polypeptide chains • Folding processes and mechanisms are mostly unknown • the 3D, native state is very expensive and time consuming to solve

  7. Modeling the Folding Process • Proteins fold in about 10 µs • Simulation would take dozens of years • Proteins are formed of thousands of atoms • Presented often as force fields • E.g. temperature, pH, covalent bonds between residues and hydrophobic effect must be taken in consideration • Proposed that the native state = minimum of potential energy curve

  8. Folding@home • Objective to study the dynamics of protein folding and misfolding and the ensuing diseases • Uses distributed computing, volunteers let their PC to be utilized when they aren’t needed • Program is a screen saver • Uses packages • AMBER, TINKER and GROMAS

  9. Ensemble Dynamics Method • Polypeptide chain is considered as a system waiting for enough free energy to overcome the free energy barrier (= the folding) • Group of several molecules M is simulated at the same time • simulation rate is then M times faster than a single simulation • The simulations are completed in hours not in years • Wait until the first one of the simulations overcomes the energy barrier • All the simulations are restarted from the new energy level

  10. Comparative modelling • aims at building a 3D model for a protein with unknown structure • relies on detectable similarities between the protein sequence being modelled (the target) and at least one empirically determined protein structure (the template) • a small change in the protein sequence usually results only in a small change in its 3D structure

  11. SWISS-MODEL • fully automated web-server for protein structure modelling • developed in 1993 • nowadays the most widely-used free web-based automated facility

  12. Using SWISS-MODEL • User-friendly • User only submits the amino acid sequnce on a web form • optionally templates can be submitted as well • Results in 15-60 min by e-mail

  13. 1Search for suitable templates 2Check sequence identity with target 3Create ProModII jobs 4Generate models with ProModII 5Energy minimisation with Gromos96 First Approach Mode (regular) First Approach Mode (with user-defined templates) Optimise Mode How SWISS-MODEL works? • Five steps that can be repated iteratively

  14. How SWISS-MODEL works? • Step 1 • search for suitable templates from ExNRL3D • program used: BLASTP2 • Step 2 • find sequences with good degree of similarity (>25%) • aling target and template sequences • program used: SIM

  15. How SWISS-MODEL works? • Step 3 • create ProModII input files • Step 4 • generate models • program used: ProModII • Step 5 • minimize energy • program used: Gromos96

  16. Are there problems with SWISS-MODEL? • Results must be concidered with care • procedure is non-experimental • no human intervention during model building • Chosen template affects the results • the more the template and the target sequence share identity the more accurate the results will be

  17. Accuracy of SWISS-MODEL

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