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Getting the most from biomolecular simulations a
practical workshop Barcelona, 10-11 July 2008
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Getting the most from biomolecular simulations a
practical workshop
Session A3 Ions, solvent, and ...
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• Biomolecules need to be simulated in the
  appropriate environment
• Ions
• Structural water
• Free solvent
• Ligands

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Adding ions

• Ions can be required to keep the 3D structure
• Structural ions (Ca2, Mg2, Zn2,...)
• Treated as ligands, require specific
  parametrization
• Counterions (Cl-, Na)
• Used to keep the system neutral or to give a
  specific ionic strength

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• Timidina quinasa HSV 1. Mecanismo de reacción

Wat
Wat
TK - ATP (Mg) - ACV
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Adding ions. Strategies

• Low charge protein system
• System is made neutral by placing the appropriate
  counter-ions at random places (VMD)
• Nucleic acid and highly charged proteins
• Ions are placed according to the electrostatic
  potential (leap)
• Different types of electrostatics could be used.

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Solvent

• Biomolecules can be simulated in gas phase, but
  this give little biologic information
• Implicit solvent models (fast but less accurate)
• Distance dependent dielectric (not a recommended
  option!!)
• GB/SA
• PB/SA (mostly used at posteriori)
• Explicit solvent models (slower)
• Variety of water models (SPC, TIP3P, TIP4P,...)
• Possibility of mixing solvents
• Structural waters (from the PDB or predicted )
  can be used.
• Do not trust the simulation to replace them!!
  Some can be at hidden places.

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Prediction of structural water
1IFC
2PTH
3EBX
4PTI
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Explicit Solvent

• Cap / spheric solvent (simpler)
• Only a drop of water around the interesting
  region is used
• Water is kept using harmonic potentials
• Cubic box (more accurate)
• Cell can be replicated in all directions
• The concepts of Volume and Pressure can be added
  to the simulation (NVT, NPT)
• Octaedric box
• Requires less water than cubic boxes

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Automatic setup?

• Other approaches exists to set-up a structure
• Reminder All automatic methods do mistakes!!
• Automatic methods only works with normal
  structures
• Always check how the structure looks like

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Automatic setup?

• Tleap and VMD have scripting capabilities
• VMD has an automatic setup option
• Extensions gt Modeling
• Add Ions, Add Solvent, Automatic PSF builder
• Pre-packed web services
• Web applications (Whatif, MDWeb)

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Web services

• Biomoby is a general standard to pack
  bioinformatics applications as small, well
  defined, web services.
• Web services perform simple operations, and can
  be chained to build complex workflows

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PDBStructure
cleanPDB

• ()
• addHydrogensPDB Service
• my pdbH addHydrogensPDB (
• 'structure' gt ss_pdb
• ) -gt 'structure'
• print OUT pdbH-gtcontent
• optimizeStructureFromNAMD_Structure Service
  (Hydrogen Minimization)
• my minH optimizeStructureFromNAMD_Structure (
• 'structure' gt pdbH,
• 'md_type', 1
• ) -gt 'structure'

addDisulphideBondsPDB
addHydrogensPDB
optimizeProteinFromNAMD_Structure
solvateProteinFromNAMD_Structure
equilibrateProteinFromNAMD_Structure
NAMDOutput
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What about ligands?

• Ligands are not usually part of forcefields, need
  parameterization
• Minimal Set charges and use standard vdw and
  bond parameters
• Complete Set also bond parameters (torsion)
• Some web sites have parameters
• http//www.pharmacy.manchester.ac.uk/bryce/amber

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Ligands

• Charge parameterization
• The usual way is fitting point charges to
  reproduce QM electrostatic potential (ESP)
• Automatic parameters
• Antechamber and GAFF
• ParaTool Molefacture (VMD)

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Practicals