Transcript lecture ppt

Lecture 2. Molecular
Force Field
Qiang Cui
Chem. 860
Spring 2009
Basic elements of Simulation
Potential Function (force field):
how atoms in
biomolecules ( ) interact with each other and how
biomolecules interact with the environment ( ).
Equilibrium statistical mechanics
Molecular Dynamics (MD)
Monte Carlo (stochastic)
Non-equilibrium statistical mechanics (MD only)
Potential Energy Function
We always assume the Born-Oppenheimer approximation
Difficult/expensive to compute accurately for large systems.
Establish simple and hopefully transferrable expressions,
parameterize based on exp. or QM calculations for a limited
number of systems, apply to complex systems.
Such simplified expressions for the potential energy function ar
often referred to as “force fields”.
Typical Force Fields for biomolecules
Non-polarizable, pair-wise additive
elec + vdW
dihedral
bond
angle
CHARMM (Karplus et al., Harvard)
AMBER (Kollman et al. UCSF)
OPLS (Jorgensen et al., Yale)
Recent review: Case & Ponder, Adv. Prot. Chem.
Vol. 66 (2003)
Flexible combinations
4
3.5
3.5
3
3
2.5
2.5
1
2.8
sum
2
2
1.9
1
sum
1.5
1.5
1
1
0.5
0.5
0
0
0
100
200
300
400
0
100
200
300
400
Non-bonded terms
1
0.9
0.8
0.7
0.6
Col
DH_0.015
DH_0.15
0.5
0.4
0.3
0.2
0.1
0
0
5
10
15
20
Example: CHARMM
Topology file: define atom types, composition of
residues [e.g., water, amino acids]
Parameter file: parameters associated with different
atoms types (non-bond)/interactions
PSF (Protein Structure File): definition of your molecule
Useful resources of automatic generation of PSF:
http://www.charmm-gui.org/
Try the PDB reader!
A closer look at the CHARMM force field
Hydrogen bonds?
Non-bond exclusion
Topology file: All-atom (22/27) vs. Polar hydrogen (19)
Parameter file (combination rules for most LJ terms)
http://www.pharmacy.umaryland.edu/faculty/amackere/force_fields.htm
Parameterization of
CHARMM
Mackerell et al., J. Phys. Chem. B 102, 3586 (1998)
J. Comp. Chem. 23, 199 (2002)
http://www.pharmacy.umaryland.edu/faculty/amackere/supplem/ParamOpt_MacKerell
.pdf
Parameterization of
CHARMM
The “marriage” to a water model (TIP3)
Implicit inclusion of polarization
http://www.pharmacy.umaryland.edu/faculty/amackere/supplem/ParamOpt_MacKerell
.pdf
What’s wrong with empirical force fields?
Pair-wise additive (effective pair-wise parameters)
Parameters may not have rigorous physical meaning
(magnitude of fixed charge, torsional energy)
Parameters may not be transferrable to other
conditions (e.g., temperature, solvent) or between
force fields or reliable for all physical observables
Difficult to deal with chemistry or complex electronic
structure (e.g., transition metal ions)
Qualitative failures for
empirical force fields?
T dependence of water density
Mahoney et al., J. Chem. Phys. 112, 8910 (2000)
Ion distribution at air-water interface
Jungwirth, Tobias, J. Phys. Chem. B 105, 10468 (2001)
What’s useful with empirical force fields?
• Computationally efficient (100,000 atoms, 10-100
ns)
• Sufficiently accurate for many properties
QuickTime™ and a
YUV420 codec decompressor
are needed to see this picture.
Schotte et al. Science, 300, 1944 (2003)
Hummer et al. PNAS, 101, 15330 (2004)
Independent Benchmark
Shirts et al. J. Chem. Phys. 119, 5740
Independent Benchmark 2
Snow et al. Annu. Rev. Biophys. Biol. Struct. 34, 43
Dynamical properties: coupled
internal/rotation
N-H bond vector property
1.2 μs
P. Maragakis et al. & D. E. Shaw, JPC, B 112, 6155 (2008)
Recent enhancements in CHARMM
• CMAP
• Polarizable force fields (Also AMBER,
TINKER, Schrodinger’s)
✴
Fluctuation charges
✴
Induced dipole model
✴
Drude oscillator
http://www.pharmacy.umaryland.edu/faculty/amackere/supplem/ParamOpt_MacKerell
Take home messages
Know your force field - for what it is
parameterized for, under what condition, most
compatible with what cutoff scheme
If used properly, even current non-polarizable
force fields give satisfying results for many
observables