Biophysical Chemistry G4170:

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Biophysical Chemistry G4170 Introduction
to Molecular Dynamics
Ruhong Zhou
IBM Thomas Watson Research Center Yorktown
Heights, NY 10598
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II. Solvation Models
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Solvation Models

• Explicit solvent models
• Fixed charge models SPC, SPC/E, TIP3P, TIP4P,
  TIP5P, ST2,
• Polarizable water models TIP4P/FQ, POL5, MCDHO,
• Implicit Solvent models
• Poisson-Boltzman solver (Delphi, Honig)
• Generalized Born Model (Still)
• Karplus EEF1 model
• Benoit Rouxs Spherical Solvent Boundary
  Potential (SSBP)

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Explicit Water Models NeededDewetting Transition
BphC Enzyme
R Zhou, X Huang, C Margulius, B Berne, Science
305, 1605, 2004
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Explicit Water modelsSPC, SPC/E, TIPnP, POL5
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Water Model Geometries
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Water Model Parameters

• SPC, SPC/E (Berendsen)
• TIP3P, TIP4P, TIP5P (Jorgensen)
• TIP4P/FQ, POL5 (Berne)

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Properties of Water Models
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Water density maximum
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Water structure comparison
M. Mahoney and W. L. Jorgensen, J. Chem. Phys.
112, 8910, 2000
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POL5 Model
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Gas-phase electrostatic properties
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Water dimer properties
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Liquid-state properties
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Water density revisited
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Computational expenseSimulations using standard
Ewald summation and 256 molecules
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Implicit Solvent ModelsPBF, GB
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Continuum Solvent Model
continuum solvent e80
e1-4 protein
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Molecular Surfaces

• Dotted line Solvent Accessible Surface (SAS)
• Solid line molecular surface (MS)
• Shaded grey area van der Waals surface

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R. Levy, JCC 2002
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Molecular Surface Colored by Potential
The molecular surface of acetyl choline esterase
molecule color coded by electrostatic potential.
the view is directly into the active site and
acetyl choline is present in a bond
representation. note the depth of the pocket, its
negative nature corresponding to the positive
charge on the acetyl choline.
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Trp-cage Folding Kinetics

• OPLS united atom Force Field
• Continuum Solvent GBSA
• Langevin dynamics
• Water viscosity g91/ps

B MD simulation C NMR structure 2.1 A Ca
RMSD Folding time 1.5ms (3.0 A cutoff) to 8.7 ms
(2.5 A cutoff)
M. Snow, B. Zagrovic, V. Pande, JACS 124, 14548,
2002
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Trp-cage Folding Structure
Blue MD simulation Grey NMR structure 0.97 A Ca
RMSD 1.4 A RMSD heavy atoms

• AMBER99 Force Field
• Continuum Solvent GBSA
• NVT ensemble

C. Simmerling, B. Strockbine, A. Roitberg, JACS
124, 11258, 2002
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Protein (un)Folding Example a b-hairpin
Protein G (2gb1)

• Res. 41-56

GEWTYDDATKTFTVTE
V. Munoz, P. Thompson, J. Hofrichter, W. Eaton,
Nature, 390, 196, 1997 R. Zhou, B. Berne and R.
Germain, PNAS, 98, 14931, 2001
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b-hairpin Folding in Various Models

• OPLSAA/SPC (explicit)
• OPLSAA/SGB
• OPLSAA/PB

R. Zhou, B. J. Berne, PNAS 99, 2002 R. Zhou, G.
Krilov, B. J. Berne, JPC, 2004
R. Zhou, et al, PNAS 98, 2001 R. Zhou, and B.
Berne, PNAS 99, 2002
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Lowest free energy structures
Explicit
SGB
PB

• Erroneous salt-bridges exist in all continuum
  solvent models
• Overly strongly salt-bridge effects expelled F50
  out of the hydrophobic core in SGB
• PB models behaves significantly better than the
  GB model
• Both PB and GB models need improvements

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Conclusion

• Water models critical to biomolecular simulations
• Implicit (continuum) solvent models very popular
  due to their faster speed
• Cautions needed for implicit solvent models,
  particularly overly strong salt-bridges
• Further improvement on implicit solvent models
  remains a hot research topic
• For certain studies, such as dewetting
  transition, explicit water molecules are still
  needed