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Amber 12 Intro PDF
Amber 12 Intro PDF
February 2011
Presentation Outline
Introduction to Amber 12
Hands-on
• Setting up a standard Amber MD Run
• Building non-standard Residues
• QM/MM: Using Amber-Gaussian
Interface
• QM/MM: Using Amber inbuilt QM
methods
What is AMBER?
Assisted
Model
AMBER Building with
Energy
Refinement
What is Amber?
“Amber” refers to two things:
1) a set of molecular mechanical force fields for the
simulation of biomolecules
2) a package of molecular simulation programs (about 50 )
which includes source code and demos
The current version of the code is Amber version 12, which is
distributed by UCSF (University of California, San
Francisco) subject to a licensing agreement
antechamber & MCPB Create force fields for general organic molecules
Version Released
12 2012
11 2010
10 2008
9 2006
8 2004
AMBER Home
• Have a look at the Amber Home Page: http://ambermd.org/
Amber Main References
A general overview of the Amber codes:
An overview of the Amber protein force fields, and how they were developed:
W. Ponder and D.A. Case. Force fields for protein simulations. Adv. Prot.
Chem. 66, 27-85 (2003).
E. Cheatham, III and M.A. Young. Molecular dynamics simulation of
nucleic acids: Successes, limitations and promise. Biopolymers 56,
232-256 (2001).
What is Amber?
QVBMM SIBFA
UFF
MM2, MM3, MM4
COSMOS-NMR AMBER
DRF90
PIPF
OPLS MMFF
ECEPP/2 CFF
GROMACS ENZYMIX
X-Pol CHARMm
CVFF QCFF/PI
GROMOS AMOEBA
CHARMM
Amber Force Field
The total Energy in Amber force field consists of
1. bonded terms relating to atoms linked by
covalent bonds and
2. nonbonded terms describing the long-range
electrostatic and van der Waals interactions:
2
Ebond stretching = ∑ K (r − r
r eq )
bonds
2
Eangle bending = ∑ Kθ (θ − θ eq )
angles
Vn
Edihedral = ∑ (1 + cos[nφ − γ ])
dihedrals 2
where Vn is the barrier to free rotation for the “natural” bond,
n is the periodicity of the rotation (number of cycles in 360°), φ
is the torsion angle and γ is the angle where the potential passes
through its minimum value
Amber Force Field: Torsion Energy
Amber Force Field: Nonbonded Terms
The nonbonded Energy terms in Amber force field
describe the long-range electrostatic and van der
Waals interactions:
Enonbonded = Eelectrostatic + EvdW
Amber Force Field: Electrostatic Energy
The Electrostatic Energy in the Amber force field
represents the pair-wise sum of the electrostatic
energies of all possible interacting non-bonded atoms i
and j:
atoms qi q j
Eelectrostatic = ∑ εR
i< j ij
- Empirical Parameters
Where Do Empirical
Parameters Come From?
Parameter Derivation: Partial Charges
In AMBER:
Connolly
1) Partial atomic charges are
Connolly static
2) Quantum chemical methods
(B3LYP/ccpVTZ//HF/
6-31G**) are used to generate
an electrostatic potential
(ESP) around a molecule on
the spheric grid
3) RESP (Restrained Electrostatic
Potential) Method is used to derive
the partial charges
req and θeq come either from experimental data (X-ray, neutron diffraction) or
Quantum Chemical calculations (geometry optimization)
In addition, charges that are not centered on atoms, but are off-center (as for
lone-pairs or "extra points") can be included in the force field.
Other Force Fields in Amber: AMOEBA
(Atomic Multipole Optimized Energetics for Biomolecular Applications)
• Atomic Multipoles: The model uses a polarizable atomic multipole description of
electrostatic interactions. Multipoles through the quadrupole are assigned to each atomic
center based on a distributed multipole analysis (DMA) derived from large basis set
molecular orbital calculations at the MP2/aug-cc-pVTZ level and the experimental geometry
of the gas-phase monomer.
where αi is the atomic polarizability and Ei,α is the sum of the fields generated by both
permanent multipoles and induced dipoles
Other Force Fields: AMOEBA
(Atomic Multipole Optimized Energetics for Biomolecular Applications)
• The functional forms for bond stretching and angle bending were taken from
the MM3 force field:
where εij is the potential well depth, ρij= Rij/R0ij with Rij as the i-j separation and R0ij the
minimum energy distance. n = 14, m = 7, δ = 0.07, γ=0.12. The combining rules are:
• The buffered 14-7 function yields a repulsive region softer than the Lennard-Jones
6-12 function but steeper than typical Buckingham exp-6 formulations.
• The buffered 14-7 form was found to outperform Lennard-Jones and Buckingham
potentials in simultaneously reproducing gas phase ab initio results and liquid
thermodynamic properties of noble gases and a series of diatomic species.
What we can do with Amber?
Molecular Dynamics Simulations
The Molecular Dynamics simulation method is based
on Newton’s second law or the equation of motion,
F=ma,
where F is the force exerted on the particle, m is its
mass and a is its acceleration
Integration of the equations of motion then yields a
trajectory that describes the positions, velocities and
accelerations of the particles as they vary with time.
From this trajectory, the average values of properties
can be determined.
MD: Melting of Ice
Human carboxyl
esterasecomplexed with morphine
MD: Translocation of DNA
This movie shows the electrophoretically-driven translocation of a 58-nucleotid DNA strand through the
transmembrane pore of alpha-hemolysin
Molecular Dynamics:
Amber MD Workhorses
SANDER - Simulated Annealing with NMR-Derived Energy
Restraints
PMEMD - Particle Mesh Ewald Molecular Dynamics
PMEMD is up to 55% faster
SANDER than SANDER
GPU
PMEMD
Molecular Dynamics:
What Are Current Simulation
Capabilities?
Time
Snapshots
Snapshots of
Representative
Structures
Snapshots of
Representative
Structures
Plotting Molecular Dynamics
Properties
Equilibration step
allows atoms and
Equilibration step MD Phase molecules to find more
natural positions with
respect to one another
Clustering
• The microscopic state of a system is defined by the atomic positions, q, and momenta,
p; these can also be considered as coordinates in a multidimensional space called
phase space
• A single point in phase space, denoted by G, describes the state of the system
• An ensemble is a collection of points in phase space satisfying the conditions of a
particular thermodynamic state.
• A Molecular Dynamics simulations generates a sequence of points in phase space as a
function of time;
• These points belong to the same ensemble, and they correspond to the different
conformations of the system and their respective momenta
Statistical Ensembles Supported in
Amber
• Microcanonical ensemble (NVE) : The thermodynamic state
characterized by a fixed number of atoms, N, a fixed volume, V,
and a fixed energy, E. This corresponds to an isolated system.
• Canonical Ensemble (NVT): This is a collection of all systems
whose thermodynamic state is characterized by a fixed number
of atoms, N, a fixed volume, V, and a fixed temperature, T.
• Isobaric-Isothermal Ensemble (NPT): This ensemble is
characterized by a fixed number of atoms, N, a fixed pressure, P,
and a fixed temperature, T.
Advanced MD Techniques in Amber
Adaptively Biased Molecular Dynamics (ABMD) method
ABMD is a method for the computation of the free energy surface of a reaction
coordinate using non-equilibrium dynamics.
• Chemical reactions,
conformational transitions, etc,
occur when the system migrates
from one local equilibrium
minimum to another, overcoming
the usually large energy barriers
that separate reagents from
products.
• The probability of such an event
occurring spontaneously depends
exponentially on the energy barrier
and easily exceeds the
computational time regime that
present-day computer technology
can afford.
Advanced Molecular Dynamics
Techniques in Amber:
Path integral molecular dynamics
Path integral molecular dynamics simulations can be used to sample equilibrium canonical
distributions using quantum dynamics rather than Newton's equations for nuclear
motion. Both equilibrium and kinetic isotope effects can be estimated via
thermodynamic integration over mass.
• Both CMD and RPMD simulations provide an efficient route for the calculation of
approximate correlation functions, which can then be related to the true quantum
correlation functions.
How to Treat Bulk System?
Bulk (“infinite”) solvent
But…
We can simulate only a relatively small
number of particles in order not to slow
down the computation.
But…
Such system is too
big to simulate… L
Central Box
No surface
Periodic Boundary Conditions
1)
Truncated octahedron
Protein-ligand complex
Evaluating Free Energies of
Binding using Amber
Evaluating Free Energies of
Binding: MM-PBSA
• The acronym MM-PBSA stands for
Molecular Mechanics- Poisson Bolzmann
Surface Area
where G is the calculated average free energy, and EMM is the average molecular
mechanical energy:
where these correspond to the bond, angle, torsion, van der Waals, and
electrostatic terms in the molecular mechanical force field, evaluated with no
nonbonded cutoff.
Evaluating Free Energies of
Binding: MM_PBSA
GPBSA is the solvation free energy calculated with a numerical solution of the
Poisson-Bolzmann equation and an estimate of the nonpolar free energy with a
simple surface area term.
-TSMM is the solute entropy, which can be estimated by quasi harmonic analysis
of the trajectory or, in selected cases, by using normal-mode analysis. This final
term is likely to be much smaller than the other two in many applications of
estimating relative free energies.
Evaluating Free Energies of
Binding: Thermodynamic integration
The thermodynamic integration (TI) technique allows to calculate the free
energy difference between two systems, A and B, by slowly interconverting the
Hamiltonian HA (representing system A) into the Hamiltonian HB (representing
system B), during the course of the simulation.
Examples:
Atom → nothing
Group of Atoms (or Molecule) → nothing
Charge on Atom → No charge on Atom
Charge on Group of Atoms (or Molecule) →
→ No charge on Group of Atoms (Molecule)
“Computational alchemy”
O O
C C
O H O
1 ∂H λ
ΔA = ∫ dλ
0 ∂λ λ
The subscript λ at the pointed angles indicates that the average should be
taken over an ensemble with Hamiltonian Hλ .
where Δλ is chosen such that the result is statistically accurate while using a
minimum of computer time.
Inclusion of Solvation Effects in
Amber
Practically all important biological
processes take place in solvent
ΔGnonel comes from the combined effect of two types of interaction: the
favorable van der Waals attraction between the solute and solvent molecules,
and the unfavorable cost of breaking the structure of the solvent (water)
around the solute.
Implicit Solvation Methods in Amber:
The Generalized Born/Surface Area
Model
Calculating ΔGnonel:
In the Amber code ΔGnonel is taken to be
proportional to the total solvent accessible
surface area (SASA) of the molecule, with a
proportionality constant derived from
experimental solvation energies of small
non-polar molecules, and uses a fast Linear
Combinations of Pairwise Overlaps (LCPO)
algorithm [J. Comput. Chem. 20, 217-230
(1999)] to compute an analytical
approximation to the surface accessible area
of the molecule.
ΔGnonel = λ • Area + b
Implicit Solvation Methods in Amber:
The Generalized Born/Surface Area
Model
Calculating ΔGel:
Within Amber GB models, each atom in a molecule is represented as a sphere of
radius ρi with a charge qi at its center; the interior of the atom is assumed to be
filled uniformly with a material of dielectric constant of 1. The molecule is
surrounded by a solvent of a high dielectric εw (80 for water at 300 K)
1 qi q j
ΔGel ≈ ΔGgb = − ∑
2 ij f gb (rij , Ri , R j )
where rij is the distance between atoms i and j, the Ri are the so-called effective
Born radii of atoms i and j, and fgb is a certain smooth function of its arguments.
A common choice of fgb is
1/ 2
2
⎡ 2 ⎛ − rij
⎞⎤
f gb = ⎢rij + Ri R j exp⎜⎜ ⎟
4 Ri R j ⎟⎥
⎣ ⎝ ⎠⎦
Implicit Solvation Methods in Amber:
ALPB (Analytical Linearized Poisson-
Boltzmann)
Based on an approximate analytical solution of the linearized Poisson-Bolzmann
equation for a sphere (Kirkwood, 1934).
The basic ALPB equation that approximates the electrostatic part of the solvation
free energy is:
1 ⎛ 1 1 ⎞ 1 ⎛ 1 αβ ⎞
ΔGel ≈ ΔGalpb = − ⎜⎜ − ⎟ ∑ij qi q j ⎜⎜ f + A ⎟⎟
2 ⎝ ε in ε ex ⎟⎠ 1 + αβ ⎝ gb ⎠
where β = εin /εex is the ratio of the internal and external dielectrics, α = 0. 571 412,
and A is the so-called effective electrostatic size of the molecule. fgb is the same
smooth function as in the GB model.
The GB approximation is then just the special case of ALPB when the solvent
dielectric is infinite; however, for finite values of solvent dielectric the ALPB tends to
be more accurate.
Grigori Sigalov, Andrew Fenley, and Alexey Onufriev, J. Chem. Phys. 124, 124902 (2006)
Grigori Sigalov, Peter Scheffel, and Alexey Onufriev, J. Chem. Phys. 122, 094511 (2005)
Implicit Solvation Methods in Amber:
Poisson-Boltzmann solver
An efficient finite-difference numerical solver is implemented for various
applications of the Poisson-Boltzmann (PB) method.
The electrostatic potential φj at atomic charge site is computed by solving the PB
equation:
where ε(r) is the dielectric constant, φ(r) is the electrostatic potential, ρ(r) is the solute
charge, zi is the charge of ion type i, ci is the number density of ion type i far from the
solute, kB is the Boltzmann constant, and T is temperature; the summation is over all
different ion types.
• This is the most rigorous method for treatment of implicit solvent in Amber
• It can be used for both static (single point) and dynamic applications.
• However, it is much slower than GB and ALPB and memory intensive for
macromolecules.
Inclusion of Solvation Effects in
Amber: RISM
RISM - Reference Interaction Site Model
RISM is an approximate solution to the Ornstein-
Zernike (OZ) equation:
where r12 is the separation between particles 1 and 2 while Ω1 and Ω2 are
their orientations relative to the vector r12. The two functions in this
relation are h, the total correlation function, and c, the direct correlation
function.
RISM: Practical Considerations
• Calculating a 3D-RISM solution for a single
solute conformation typically requires about
100 times more computer time than the same
calculation with explicit solvent or PB.
• Memory: anywhere from a few megabytes
for the smallest solutes to gigabytes for large
complexes
Exploring Conformational Space
of Biomolecules
Conformational Space
of Biomolecules Can Be Very Complex
Exploring Conformational Space
of Biomolecules
• Due to this property of the free energy landscape,
efficient computational approaches for searching
for low-energy minima in these complex systems
present a great challenge.
Exploring Conformational Space:
Simulating Annealing
Temperature
Time
Energy Profile Local Minima
Exploring Conformational Space:
REMD
REMD stands for the Replica Exchange Method Dynamics
In REMD several noninteracting copies (replicas) are independently and
simultaneously simulated at different temperatures.
Replica 1, T1
Replica 2, T2
Replica N, TN
Replica 2, T2
Replica N, TN
Suitable for small and medium size Suitable for large molecular
systems systems
Why Do We Need a Hybrid QM/MM
Approach?
The main bottleneck of quantum chemical methods is that they are CPU and memory
hungry.
For example, for small peptide of 126 atoms one energy evaluation requires:
CPU Time Memory
⇒ the van der Waals terms on the MM atoms often provide the only difference in the
interactions of one atom type versus another, i.e. chloride and bromide ions both
have unit negative charge and only differ in their van der Waals terms.
A Hybrid QM/MM Model
So, it is quite reasonable to attribute the van der Waals parameters (as it is in the MM
method) to every QM atom and the Hamiltonian describing the interaction between the
QM and MM atoms can have a form:
electrons MM atoms
Qj nuclei MM atoms
Z iQ j nuclei MM atoms
⎪ Aij Bij ⎫
⎧ ⎪
Hˆ QM / MM = − ∑ ∑ + ∑ ∑ +∑ ∑ ⎨ 12 − 6 ⎬
i j rij i j Rij i j ⎩ Rij Rij ⎪
⎪ ⎭
The van der Waals term models also electronic repulsion and dispersion interactions,
which do not exist between QM and MM atoms because MM atoms possess no
explicit electrons.
Hˆ = Hˆ QM + Hˆ QM / MM + Hˆ MM
electrons MM atoms
Qj nuclei MM atoms
Z iQ j nuclei MM atoms
⎪ Aij Bij ⎫
⎧ ⎪
Hˆ QM / MM = − ∑ ∑ + ∑ ∑ +∑ ∑ ⎨ 12 − 6 ⎬
i j rij i j Rij i j ⎪ R
⎩ ij Rij ⎪
⎭
A “standard” MM force field can be used to determine the MM energy. For example,
AMBER-like force field has a form:
Vϕ
∑ (1 + cos(nϕ ))
dihedrals 2
Choice of QM method
... is a compromise between computational efficiency and practicality and the desired
chemical accuracy.
The main advantage of semi-empirical QM methods is that their computational
efficiency is orders of magnitude greater than either the density functional or ab initio
methods
Calculation times (in time units)
O F
O F
P O F
O O
N N
O O O O
5) By varying the radii in the van der Waals terms to reproduce experimental
free energies of solvation using MD simulations.
P.L. Cummins, J.E. Gready, J.Comp.Chem., 18(1997), 1496-512.
Dividing Covalent Bonds across the
QM and MM Regions
MM Region
O A. Warshel, M. Levitt // Theoretical Studies of
QM Region Enzymic Reactions: Dielectric, Electrostatic and
steric stabilization of the carbonium ion in the
O reaction of lysozyme. // J.Mol.Biol.
103 (1976), 227-249
Frontier QM
Frontier MM V. Thery, D. Rinaldi, J.-L. Rivail, B. Maigret,
Atom
Atom
G.G. Ferenczy, J.Comp.Chem. 15 (1995), 269
Frontier MM
Atom
Dividing Covalent Bonds across the
QM and MM Regions
Using “link” atoms
ADF Gaussian
(Amsterdam Density Functional)
GAMESS-US Orca
NWChem TeraChem
QM/MM calculations: ab initio
and DFT methods
Mechanical and electrostatic embedding:
• Gaussian
• Orca
• TeraChem
Mechanical embedding:
• ADF
• GAMESS-US
• NWChem
Importance of Visualization
http://www.openrasmol.org/
Freeware Visualization Programs:
VMD (Visual Molecular Dynamics)
http://www.csc.fi/gopenmol/
http://sirius.sdsc.edu/
Freeware Visualization Programs:
Chimera
http://www.cgl.ucsf.edu/chimera/
Freeware Visualization Programs:
MD Display
Tripos (www.tripos.com)
Accelrys (http://www.accelrys.com)
and others…
Learning Amber
Amber Basic Tutorials
• http://ambermd.org/tutorials/
Using VMD with AMBER Brief introduction to using VMD for visualising AMBER
inpcrd, restrt and trajectory files
Folding TRP Cage Vreating structures using XLeap followed by running heating
and long MD simulations to conduct protein folding
experiments. Advanced analysis: RMSd fitting, mdcrd to
binpos conversion, average structure calculation, hydrogen
bond analysis and dihedral angle tracking using ptraj
Demo of Ptraj Commands How to use AMBER's ptraj analysis program to analyse a
peptide simulation and gather a range of statistics from the
trajectory.
Visualizing Amber how to use Sirius visualization software to display and analyze
Trajectories with Sirius AMBER MD trajectory files
Amber Advanced Tutorials
• http://ambermd.org/tutorials/
Setting up an Advanced Preparing a system, for simulation with sander, that contains
System (Including Charge several non-standard residues
Derivation)
… and other
Resume