Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond...
Transcript of Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond...
![Page 1: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/1.jpg)
Force Fields for Classical Molecular Dynamics simulations of Biomolecules
Emad Tajkhorshid
Beckman InstituteDepartments of Biochemistry
Center for Biophysics and Computational BiologyUniversity of Illinois at Urbana-Champaign
![Page 2: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/2.jpg)
Classical Force Field Parameters• Topology and structure files • Parameter files• Where do all the numbers needed by an
MD code come from? • Where to find these numbers and how to
change them if needed. • How to make topology files for ligands,
cofactors, special amino acids, …• How to develop / put together missing
parameters.
![Page 3: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/3.jpg)
Classical Molecular Dynamics
ij
ji
rqq
rU04
1)(πε
=
Coulomb interactionU(r) = ✏ij [(
Rmin,ij
rij)12 � (
Rmin,ij
rij)6]
![Page 4: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/4.jpg)
Classical Molecular Dynamics
Bond definitions, atom types, atom names, parameters, ….
![Page 5: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/5.jpg)
Energy Terms Described in
Bond Angle
Dihedral Improper
![Page 6: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/6.jpg)
The Potential Energy Function
Ubond = oscillations about the equilibrium bond lengthUangle = oscillations of 3 atoms about an equilibrium bond angleUdihedral = torsional rotation of 4 atoms about a central bondUnonbond = non-bonded energy terms (electrostatics and Lenard-Jones)
![Page 7: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/7.jpg)
€
Vbond = Kb b − bo( )2€
Vangle = Kθ θ −θo( )2
))cos(1( δφφ −+= nKVdihedral
Interactions between bonded atoms
![Page 8: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/8.jpg)
0
100.0000
200.0000
300.0000
400.0000
0.5 1.0 1.5 2.0 2.5
Bond Energy versus Bond length
Pote
ntia
l Ene
rgy,
kca
l/mol
Bond length, Å
Single BondDouble BondTriple Bond
Chemical type Kbond bo
C-C 100 kcal/mole/Å 2 1.5 Å
C=C 200 kcal/mole/Å 2 1.3 Å
C=C 400 kcal/mole/Å 2 1.2 Å
( )2obbond bbKV −=
Bond angles and improper terms have similar quadratic forms, but with softer spring constants. The force constants can be obtained from vibrational analysis of the molecule (experimentally or theoretically).
![Page 9: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/9.jpg)
0
5.0000
10.0000
15.0000
20.0000
0 60 120 180 240 300 360
Dihedral energy versus dihedral angle
Pote
ntia
l Ene
rgy,
kca
l/mol
Dihedral Angle, degrees
K=10, n=1K=5, n=2K=2.5, N=3
))cos(1( δφφ −+= nKVdihedral
δ = 0˚
Dihedral Potential
![Page 10: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/10.jpg)
X
non�bonded
qiqj
4⇡Drij+ ✏ij [(
Rmin,ij
rij)12 � (
Rmin,ij
rij)6]
qi: partial atomic chargeD: dielectric constantε: Lennard-Jones (LJ, vdW) well-depthRmin: LJ radius (Rmin/2 in CHARMM)Combining rules (CHARMM, Amber) Rmin i,j = Rmin i + Rmin j εi,j = SQRT(εi * εj )
Nonbonded Parameters
![Page 11: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/11.jpg)
-100.0000
-80.0000
-60.0000
-40.0000
-20.0000
0
20.0000
40.0000
60.0000
80.0000
100.0000
0 1.0000 2.0000 3.0000 4.0000 5.0000 6.0000 7.0000 8.0000
Electrostatic Energy versus Distance
Inte
ract
ion
ener
gy, k
cal/m
ol
Distance, Å
q1=1, q2=1 q1=-1, q2=1
From MacKerellNote that the effect is long range.
![Page 12: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/12.jpg)
CHARMM- Mulliken* AMBER(ESP/RESP)
Partial atomic charges
C O H N0.5-0.5 0.35
-0.45
*Modifications based on interactions with TIP3 water
Charge Fitting Strategy
![Page 13: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/13.jpg)
CHARMM Potential Function
geometry
parameters
PDB file
PSF file
Parameter file
Topology
![Page 14: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/14.jpg)
File Format/Structure
• The structure of a pdb file• The structure of a psf file• The topology file• The parameter file• Connection to potential energy terms
![Page 15: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/15.jpg)
ATOM 22 N ALA B 3 -4.073 -7.587 -2.708 1.00 0.00 BH ATOM 23 HN ALA B 3 -3.813 -6.675 -3.125 1.00 0.00 BH ATOM 24 CA ALA B 3 -4.615 -7.557 -1.309 1.00 0.00 BH ATOM 25 HA ALA B 3 -4.323 -8.453 -0.704 1.00 0.00 BH ATOM 26 CB ALA B 3 -4.137 -6.277 -0.676 1.00 0.00 BH ATOM 27 HB1 ALA B 3 -3.128 -5.950 -0.907 1.00 0.00 BH ATOM 28 HB2 ALA B 3 -4.724 -5.439 -1.015 1.00 0.00 BH ATOM 29 HB3 ALA B 3 -4.360 -6.338 0.393 1.00 0.00 BH ATOM 30 C ALA B 3 -6.187 -7.538 -1.357 1.00 0.00 BH ATOM 31 O ALA B 3 -6.854 -6.553 -1.264 1.00 0.00 BH ATOM 32 N ALA B 4 -6.697 -8.715 -1.643 1.00 0.00 BH ATOM 33 HN ALA B 4 -6.023 -9.463 -1.751 1.00 0.00 BH ATOM 34 CA ALA B 4 -8.105 -9.096 -1.934 1.00 0.00 BH ATOM 35 HA ALA B 4 -8.287 -8.878 -3.003 1.00 0.00 BH ATOM 36 CB ALA B 4 -8.214 -10.604 -1.704 1.00 0.00 BH ATOM 37 HB1 ALA B 4 -7.493 -11.205 -2.379 1.00 0.00 BH ATOM 38 HB2 ALA B 4 -8.016 -10.861 -0.665 1.00 0.00 BH ATOM 39 HB3 ALA B 4 -9.245 -10.914 -1.986 1.00 0.00 BH ATOM 40 C ALA B 4 -9.226 -8.438 -1.091 1.00 0.00 BH ATOM 41 O ALA B 4 -10.207 -7.958 -1.667 1.00 0.00 BH 00000000000000000000000000000000000000000000000000000000000000000000000000 10 20 30 40 50 60 70
indexname
resnamechain
resid X Y Z segname
>>> It is an ascii, fixed-format file <<<
Structure of a PDB file
“No connectivity information”
![Page 16: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/16.jpg)
Looking at File Structures
• PDB file
• Topology file
• PSF file
• Parameter file
![Page 17: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/17.jpg)
Check if it has been parameterized by somebody else
Literature
Minimal optimization By analogy (direct transfer of known parameters) Quick, starting point
Maximal optimization Time-consuming Requires appropriate experimental and target data
Choice based on goal of the calculations Minimal database screening NMR/X-ray structure determination Maximal free energy calculations, mechanistic studies, subtle environmental effects
Parameter Optimization Strategies
![Page 18: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/18.jpg)
• Identify previously parameterized compounds• Access topology information – assign atom types,
connectivity, and charges – annotate changes
CHARMM topology (parameter files)
top_all22_model.inp (par_all22_prot.inp)top_all22_prot.inp (par_all22_prot.inp)top_all22_sugar.inp (par_all22_sugar.inp)top_all27_lipid.rtf (par_all27_lipid.prm)top_all27_na.rtf (par_all27_na.prm)top_all27_na_lipid.rtf (par_all27_na_lipid.prm)top_all27_prot_lipid.rtf (par_all27_prot_lipid.prm)top_all27_prot_na.rtf (par_all27_prot_na.prm)toph19.inp (param19.inp)
NA and lipid force fields have new LJ parameters for the alkanes, representing increased optimization of the protein alkane parameters. Tests have shown that these are compatible (e.g. in protein-nucleic acid simulations). For new systems is suggested that the new LJ parameters be used. Note that only the LJ parameters were changed; the internal parameters are identical
Getting Started
www.pharmacy.umaryland.edu/faculty/amackere/force_fields.htm
![Page 19: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/19.jpg)
A Brief Overview ofThe Force Field Toolkit (ffTK)
Dr. Christopher G. MayneTajkhorshid Group
February 13th, 2012
![Page 20: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/20.jpg)
Available Methods for Obtaining Parameters
Analogy
ParamChem
SwissParam
MATCH
http://swissparam.ch/
Zoete et al.; J. Comp. Chem. 32(11) 2011, pp.2359-2368
https://www.paramchem.org/
Yesselman et al.; J. Comp. Chem. 33(2) 2012, pp.189-202
http://brooks.chem.lsa.umich.edu/software
(Re-use of parameters from similar structures)
http://gaamp.lcrc.anl.gov/para-fit.htmlGAAMP
ParaTool http://www.ks.uiuc.edu/Research/vmd/plugins/paratool/
Development
ffTK http://www.ks.uiuc.edu/Research/vmd/plugins/fftk/
![Page 21: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/21.jpg)
An Example: Acetaminophen
HO
NH
O
MeMe Me
Tyrosine
NMA orACE-patch
New Types
![Page 22: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/22.jpg)
An Example: Acetaminophen
HO
NH
O
MeMe Me
Tyrosine
NMA orACE-patch
New Types
New Charges
BondsAngleDihedrals
![Page 23: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/23.jpg)
update PSF
update PAR
update PAR
build init PAR
update PDB
Calculation Action
ffTK Facilitates the Parameterization Workflow
System Preparation
Charges
Bonds & Angles
Dihedrals / Torsions
Water Interaction En. (QM)
Charge Optimization
Frequency Calculation (QM)
Transform Hessian
Torsion Scan (QM)
Torsion Optimization
Find Missing Parameters
Geometry Optimization (QM)PSF/PDB
PAR File
![Page 24: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/24.jpg)
ffTK Interface
tasks divided into separate tabs
event log provides visual feedback
arrows/triangles indicate collapsable elements
entry boxes to hold variables
treeview boxes to hold lists
file dialog buttons
action buttons
action menus
![Page 25: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/25.jpg)
Setup necessary QM calculations
Visualize calculation input/output
Multidimensional optimizationof developing parameters
Read/Write files (pdb, par, log, gau)
Full documentation online:http://www.ks.uiuc.edu
/Research/vmd/plugins/fftk/
ffTK 1.0 is Available in VMD 1.9.1
Tutorial is under development
![Page 26: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/26.jpg)
• Most important aspect for ligands
• Different force fields might take different philosophies• AMBER: RESP charges at the HF/6-31G level
• Overestimation of dipole moments• Easier to set up
• CHARMM: Interaction based optimization• TIP3P water representing the environment• Could be very difficult to set up
• Conformation dependence of partial charges• Lack of polarization
• Try to be consistent within the force field
• pKa calculations for titratable residues
Partial Charge Assignment
![Page 27: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/27.jpg)
Parameterization of unsaturated lipids • All C=C bonds are cis, what does rotation about neighboring
single bonds look like?
Courtesy of Scott Feller, Wabash College
![Page 28: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/28.jpg)
DHA conformations from MD• rotational barriers are
extremely small• many conformers are
accessible w/ short lifetimes
Courtesy of Scott Feller, Wabash College
![Page 29: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/29.jpg)
Dynamics of saturated vs. polyunsaturated lipid chains
• sn1 stearic acid = blue• sn2 DHA = yellow• 500 ps of dynamics
Movie courtesy of Mauricio Carrillo Tripp
Courtesy of Scott Feller, Wabash College
![Page 30: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/30.jpg)
Lipid-protein interactions• Radial distribution around protein shows distinct layering of acyl chains
• DHA penetrates deeper into the protein surface
Courtesy of Scott Feller, Wabash College
![Page 31: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/31.jpg)
Lipid-protein interactions• Decomposition of non-bonded interaction shows rhodopsin is strongly
attracted to unsaturated chain• All hydrophobic residues are stabilized by DHA
resname UDHA Ustearic ratioPHE -44.9 -22.6 2.0ILE -30.0 -10.1 3.0VAL -24.0 -9.6 2.5LEU -23.1 -13.0 1.8MET -22.8 -9.7 2.4TYR -18.6 -10.4 1.8ALA -11.4 -3.0 3.8TRP -10.3 -2.4 4.2
Courtesy of Scott Feller, Wabash College
![Page 32: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/32.jpg)
Origin of protein:DHA attraction
• Flexibility of the DHA chain allows solvation of the rough protein surface to occur with little intra-molecular energy cost
Courtesy of Scott Feller, Wabash College
![Page 33: Force Fields for Classical Molecular Dynamics simulations of ...Classical Molecular Dynamics Bond definitions, atom types, atom names, parameters, …. Energy Terms Described in Bond](https://reader033.fdocuments.net/reader033/viewer/2022051901/5ff08d609a8ed5764e65cfc7/html5/thumbnails/33.jpg)
Major Recent Developments • New set of lipid force field parameters for
CHARMM (CHARMM32+)–Pastor, B. Brooks, MacKerell
• Polarizable force field–Roux, MacKerell