Foldinghome and SWISSMODEL

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Folding_at_home and SWISS-MODEL
Two Different Approaches to Protein Structure
Modeling

• Taru Tukiainen ja Sini Sipponen
• S-114.2500
• 13.12.2006

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Outline

• Introduction to protein modelling
• Modelling the folding process with Folding_at_home
• Comparative modelling with SWISS-MODEL

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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

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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

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Misfolding

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

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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

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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

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Folding_at_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 arent needed
• Program is a screen saver
• Uses packages
• AMBER, TINKER and GROMAS

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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

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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

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SWISS-MODEL

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

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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

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How SWISS-MODEL works?

• Five steps that can be repated iteratively

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How SWISS-MODEL works?

• Step 1
• search for suitable templates from ExNRL3D
• program used BLASTP2
• Step 2
• find sequences with good degree of similarity
  (gt25)
• aling target and template sequences
• program used SIM

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How SWISS-MODEL works?

• Step 3
• create ProModII input files
• Step 4
• generate models
• program used ProModII
• Step 5
• minimize energy
• program used Gromos96

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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

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Accuracy of SWISS-MODEL