aaa-master-ISDD-2.txt

/**
\page master-ISDD-2 Master ISDD tutorial: Metadynamics simulations with PLUMED

\section master-ISDD-2-aims Aims

The aim of this tutorial is to train users to perform metadynamics simulations with PLUMED.

\section master-ISDD-2-objectives Objectives

Once this tutorial is completed students will be able to:
- Write the PLUMED input file to perform metadynamics simulations
- Calculate the free energy from a metadynamics run
- Monitor the behavior of variables in a metadynamics run

\section master-ISDD-2-resources Resources

Before starting the tutorial, please create a separate directory, named `handson_2`, and enter it:
\verbatim
mkdir handson_2 
cd handson_2
\endverbatim

The \tarball{master-ISDD-2} for this project contains the following files:
- diala.pdb: a PDB file for alanine dipeptide in vacuo
- topol.tpr: a GROMACS run file to perform MD of alanine dipeptide

This tutorial has been tested on version 2.5.1.

\section master-ISDD-2-intro Introduction

We have seen that PLUMED can be used to compute collective variables. However, PLUMED
is most often use to add forces on the collective variables. To this aim,
we have implemented a variety of possible biases acting on collective variables.
The complete documentation for
all the biasing methods available in PLUMED can be found at the \ref Bias page.
In the following we will see how to build an adaptive bias potential with metadynamics.
Here you can find a brief recap of the metadynamics theory.

\hidden{Summary of theory}

In metadynamics, an external history-dependent bias potential is constructed in the space of 
a few selected degrees of freedom \f$ \vec{s}({q})\f$, generally called collective variables (CVs) \cite metad.
This potential is built as a sum of Gaussian kernels deposited along the trajectory in the CVs space:

\f[
V(\vec{s},t) = \sum_{ k \tau < t} W(k \tau)
\exp\left(
-\sum_{i=1}^{d} \frac{(s_i-s_i({q}(k \tau)))^2}{2\sigma_i^2}
\right).
\f]

where \f$ \tau \f$ is the Gaussian deposition stride, 
\f$ \sigma_i \f$ the width of the Gaussian for the \f$i\f$th CV, and \f$ W(k \tau) \f$ the
height of the Gaussian. The effect of the metadynamics bias potential is to push the system away 
from local minima into visiting new regions of the phase space. Furthermore, in the long
time limit, the bias potential converges to minus the free energy as a function of the CVs:

\f[
V(\vec{s},t\rightarrow \infty) = -F(\vec{s}) + C.
\f]

In standard metadynamics, Gaussian kernels of constant height are added for the entire course of a 
simulation. As a result, the system is eventually pushed to explore high free-energy regions
and the estimate of the free energy calculated from the bias potential oscillates around
the real value. 
In well-tempered metadynamics \cite Barducci:2008, the height of the Gaussian 
is decreased with simulation time according to:

\f[
 W (k \tau ) = W_0 \exp \left( -\frac{V(\vec{s}({q}(k \tau)),k \tau)}{k_B\Delta T} \right ),
\f]

where \f$ W_0 \f$ is an initial Gaussian height, \f$ \Delta T \f$ an input parameter 
with the dimension of a temperature, and \f$ k_B \f$ the Boltzmann constant. 
With this rescaling of the Gaussian height, the bias potential smoothly converges in the long time limit,
but it does not fully compensate the underlying free energy:

\f[
V(\vec{s},t\rightarrow \infty) = -\frac{\Delta T}{T+\Delta T}F(\vec{s}) + C.
\f]

where \f$ T \f$ is the temperature of the system.
In the long time limit, the CVs thus sample an ensemble
at a temperature \f$ T+\Delta T \f$ which is higher than the system temperature \f$ T \f$.
The parameter \f$ \Delta T \f$ can be chosen to regulate the extent of free-energy exploration:
 \f$ \Delta T = 0\f$ corresponds to standard MD, \f$ \Delta T \rightarrow\infty\f$ to standard
metadynamics. In well-tempered metadynamics literature and in PLUMED, you will often encounter
the term "bias factor" which is the ratio between the temperature of the CVs (\f$ T+\Delta T \f$) 
and the system temperature (\f$ T \f$):

\f[
\gamma = \frac{T+\Delta T}{T}.
\f]

The bias factor should thus be carefully chosen in order for the relevant free-energy barriers to be crossed
efficiently in the time scale of the simulation.
 
Additional information can be found in the several review papers on metadynamics 
\cite gerv-laio09review \cite WCMS:WCMS31 \cite WCMS:WCMS1103 \cite bussi2015free.

\endhidden

We will play with a toy system, alanine dipeptide simulated in vacuo using the AMBER99SB-ILDN 
force field (see Fig. \ref master-ISDD-2-ala-fig).
This rather simple molecule is useful to understand data analysis and free-energy methods.
This system is a nice example because it presents two metastable states separated by a high free-energy barrier.
It is conventional use to characterize the two states in terms of Ramachandran dihedral angles, which are denoted with \f$ \Phi \f$ and \f$ \Psi \f$ in Fig. \ref master-ISDD-2-transition-fig .

\anchor master-ISDD-2-ala-fig
\image html belfast-2-ala.png "The molecule of the day: alanine dipeptide."

\anchor master-ISDD-2-transition-fig
\image html belfast-2-transition.png "Two metastable states of alanine dipeptide are characterized by their Ramachandran dihedral angles."

\section master-ISDD-2-ex Exercises

\subsection master-ISDD-2-ex-1 Exercise 1: my first metadynamics calculation

In this exercise we will setup and perform a well-tempered metadynamics run using the backbone dihedral \f$ \phi \f$
as collective variable. During the calculation, we will also monitor the behavior of the other backbone dihedral \f$ \psi \f$.

Here you can find a sample `plumed.dat` file that you can use as a template.
Whenever you see an highlighted \highlight{FILL} string, this is a string that you should replace.

\plumedfile
# vim:ft=plumed
MOLINFO STRUCTURE=diala.pdb
# Compute the backbone dihedral angle phi, defined by atoms C-N-CA-C
# you might want to use MOLINFO shortcuts
phi: TORSION ATOMS=__FILL__
# Compute the backbone dihedral angle psi, defined by atoms N-CA-C-N
psi: TORSION ATOMS=__FILL__

# Activate well-tempered metadynamics in phi
metad: __FILL__ ARG=__FILL__ ...
# Deposit a Gaussian every 500 time steps, with initial height equal to 1.2 kJ/mol
  PACE=500 HEIGHT=1.2 
# the bias factor should be wisely chosen
  BIASFACTOR=__FILL__
# Gaussian width (sigma) should be chosen based on CV fluctuation in unbiased run
  SIGMA=__FILL__
# Gaussians will be written to file and also stored on grid
  FILE=HILLS GRID_MIN=-pi GRID_MAX=pi
...

# Print both collective variables and the value of the bias potential on COLVAR file
PRINT ARG=__FILL__ FILE=COLVAR STRIDE=10
\endplumedfile

The syntax for the command \ref METAD is simple.
The directive is followed by a keyword ARG followed by the labels of the CVs
on which the metadynamics potential will act.
The keyword PACE determines the stride of Gaussian deposition in number of time steps,
while the keyword HEIGHT specifies the height of the Gaussian in kJ/mol. For each CVs, one has
to specify the width of the Gaussian by using the keyword SIGMA. Gaussian will be written
to the file indicated by the keyword FILE.

In this example, the bias potential will be stored on a grid, whose boundaries are specified by the keywords GRID_MIN and GRID_MAX.
Notice that you can provide either the number of bins for every collective variable (GRID_BIN) or
the desired grid spacing (GRID_SPACING). In case you provide both PLUMED will use
the most conservative choice (highest number of bins) for each dimension.
In case you do not provide any information about bin size (neither GRID_BIN nor GRID_SPACING)
and if Gaussian width is fixed, PLUMED will use 1/5 of the Gaussian width as grid spacing.
This default choice should be reasonable for most applications.

Once your `plumed.dat` file is complete, you can run a 10-ns long metadynamics simulations with the following command
\verbatim
> gmx mdrun -s topol.tpr -nsteps 5000000 -plumed plumed.dat 
\endverbatim

During the metadynamics simulation, PLUMED will create two files, named COLVAR and HILLS.
The COLVAR file contains all the information specified by the PRINT command, in this case
the value of the CVs every 10 steps of simulation, along with the current value of the metadynamics bias potential. 
We can use `gnuplot` to visualize the behavior of the CV during the simulation, as reported in the COLVAR file:

\verbatim
gnuplot> p "COLVAR" u 1:2
\endverbatim

\anchor master-ISDD-2-phi-fig
\image html munster-metad-phi.png "Time evolution of the metadynamics CV during the first 2 ns of a metadynamics simulation of alanine dipeptide in vacuum."

By inspecting Figure \ref master-ISDD-2-phi-fig, we can see that the system is initialized in one of the two metastable
states of alanine dipeptide. After a while (t=0.1 ns), the system is pushed
by the metadynamics bias potential to visit the other local minimum. As the simulation continues,
the bias potential fills the underlying free-energy landscape, and the system is able to diffuse in the
entire phase space.

The HILLS file contains a list of the Gaussian kernels deposited along the simulation.
If we give a look at the header of this file, we can find relevant information about its content:

\verbatim
#! FIELDS time phi sigma_phi height biasf
#! SET multivariate false
#! SET min_phi -pi
#! SET max_phi pi
\endverbatim 

The line starting with FIELDS tells us what is displayed in the various columns of the HILLS file:
the simulation time, the instantaneous value of \f$ \phi \f$, the Gaussian width and height, and the bias factor. 
We can use the HILLS file to visualize the decrease of the Gaussian height during the simulation,
according to the well-tempered recipe:

\anchor master-ISDD-2-phihills-fig
\image html munster-metad-phihills.png "Time evolution of the Gaussian height."

If we look carefully at the scale of the y-axis, we will notice that in the beginning the value
of the Gaussian height is higher than the initial height specified in the input file, which should be 1.2 kJ/mol.
In fact, this column reports the height of the Gaussian scaled by the pre-factor that
in well-tempered metadynamics relates the bias potential to the free energy.

\subsection master-ISDD-2-ex-2 Exercise 2: estimating the free energy 

One can estimate the free energy as a function of the metadynamics CVs directly from the metadynamics
bias potential. In order to do so, the utility \ref sum_hills should be used to sum the Gaussian kernels
deposited during the simulation and stored in the HILLS file.  
To calculate the free energy as a function of \f$ \phi \f$, it is sufficient to use the following command line:

\verbatim
plumed sum_hills --hills HILLS
\endverbatim

The command above generates a file called `fes.dat` in which the free-energy surface as function
of \f$ \phi \f$ is calculated on a regular grid. One can modify the default name for the free energy file,
as well as the boundaries and bin size of the grid, by using the following options of \ref sum_hills :

\verbatim
--outfile - specify the outputfile for sumhills
--min - the lower bounds for the grid
--max - the upper bounds for the grid
--bin - the number of bins for the grid
--spacing - grid spacing, alternative to the number of bins
\endverbatim 

The result should look like this:

\anchor master-ISDD-2-metad-phifes-fig
\image html munster-metad-phifes.png "Estimate of the free energy as a function of the dihedral phi from a 10ns-long well-tempered metadynamics simulation."

To assess the convergence of a metadynamics simulation, one can calculate the estimate of the free energy as a function
of simulation time. At convergence, the reconstructed profiles should be similar.
The option \-\-stride should be used to give an estimate of the free energy every N Gaussian kernels deposited, and
the option \-\-mintozero can be used to align the profiles by setting the global minimum to zero.
If we use the following command line:

\verbatim
plumed sum_hills --hills HILLS --stride 100 --mintozero
\endverbatim

one free energy is calculated every 100 Gaussian kernels deposited, and the global minimum is set to zero in all profiles.
The resulting plot should look like the following:

\anchor master-ISDD-2-metad-phifest-fig
\image html munster-metad-phifest.png "Estimates of the free energy as a function of the dihedral phi calculated every 100 Gaussian kernels deposited."

These two qualitative observations:
- the system is diffusing efficiently in the collective variable space (Figure \ref master-ISDD-2-phi-fig) 
- the estimated free energy does not change significantly as a function of time (Figure \ref master-ISDD-2-metad-phifest-fig) 

suggest that the simulation most likely converged. 

\warning The fact that the Gaussian height is decreasing to zero should not be used as a measure of convergence
of your metadynamics simulation!

\note The two observations above are necessary, but qualitative conditions for convergence.
For a quantitative analysis, please have a look at one of our tutorials about error analysis, such as 
\ref trieste-4 . 

\subsection master-ISDD-2-ex-4 Exercise 3: reweighting

In the previous exercise we biased \f$\phi\f$ and compute the free energy as a function of
the same variable. Many times you want to decide which variable you want to analyze _after_
having performed a simulation. In order to do so you must reweight your simulation.

There are multiple ways to reweight a metadynamics simulations.
In order to calculate these weights, we can use either of these
two approaches:

1) Weights are calculated by considering the time-dependence of the metadynamics bias
   potential \cite Tiwary_jp504920s;

2) Weights are calculated using the metadynamics bias potential obtained at the end of the
   simulation and assuming a constant bias during the entire course of the simulation \cite Branduardi:2012dl.

In this exercise we will use the umbrella-sampling-like reweighting approach (Method 2).
In order to compute the weights we will use the \ref driver tool.

First of all, prepare a `plumed_reweight.dat` file that is identical to the one you used
for running your simulation but add the keyword `RESTART=YES` to the \ref METAD command.
This will make this action behave as if PLUMED was restarting. It will thus
read the already accumulated hills and continue adding more.
In addition, set hills height to zero and the pace to a large number.
This will actually avoid adding new hills (and even if they are added they will have
zero height). Finally, change the \ref PRINT statement so that you
write every frame (`STRIDE=1`) and that, in addition to `phi` and `psi`,
you also write `metad.bias.

\plumedfile
__FILL__ # here goes the definitions of the CVs

# Activate well-tempered metadynamics in phi
metad: __FILL__ ARG=__FILL__ ...
# Deposit a Gaussian every 500 time steps, with initial height equal to 1.2 kJ/mol
  PACE=10000000 HEIGHT=0.0 # <- this is the new stuff!
# the bias factor should be wisely chosen
  BIASFACTOR=__FILL__
# Gaussian width (sigma) should be chosen based on CV fluctuation in unbiased run
  SIGMA=__FILL__
# Gaussians will be written to file and also stored on grid
  FILE=HILLS GRID_MIN=-pi GRID_MAX=pi
# Say that METAD should be restarting
  RESTART=YES # <- this is the new stuff!
...

PRINT ARG=phi,psi,metad.bias FILE=COLVAR STRIDE=1  # <- also change this one!
\endplumedfile

Then run the driver using this command
\verbatim
> plumed driver --ixtc traj_comp.xtc --plumed plumed.dat --kt 2.5
\endverbatim
Notice that you have to specify the value of \f$k_BT\f$ in energy units. While running your simulation
this information was taken from the MD code.

As a result, PLUMED will produce a new COLVAR file with an additional column. The beginning
of the file should look like this:
\verbatim
#! FIELDS time phi psi metad.bias
#! SET min_phi -pi
#! SET max_phi pi
#! SET min_psi -pi
#! SET max_psi pi
 0.000000 -1.497988 0.273498 110.625670
 1.000000 -1.449714 0.576594 110.873141
 2.000000 -1.209587 0.831417 109.742353
 3.000000 -1.475975 1.279726 110.752327
\endverbatim

The last column will give as, in energy units, the logarithm of the weight of each frame.
You can easily obtain the weight of each frame using the expression \f$w\propto\exp\left(\frac{V(s)}{k_BT}\right)\f$.
You might want to read the `COLVAR` file in python and compute a weighted histogram.

If you want PLUMED to do the histograms for you, you can just add the following
lines to the PLUMED input file:

\plumedfile
as: REWEIGHT_BIAS ARG=__FILL__

hhphi: HISTOGRAM ARG=phi STRIDE=50 GRID_MIN=-pi GRID_MAX=pi GRID_BIN=600 BANDWIDTH=0.1 LOGWEIGHTS=as
hhpsi: HISTOGRAM ARG=psi STRIDE=50 GRID_MIN=-pi GRID_MAX=pi GRID_BIN=600 BANDWIDTH=0.1 LOGWEIGHTS=as
ffphi: CONVERT_TO_FES GRID=hhphi
ffpsi: CONVERT_TO_FES GRID=hhpsi

DUMPGRID GRID=ffphi FILE=ffphi.dat
DUMPGRID GRID=ffpsi FILE=ffpsi.dat
\endplumedfile

and plot the result using gnuplot.

\verbatim
gnuplot> p "ffphi.dat"
gnuplot> p "ffpsi.dat"
\endverbatim

\section master-ISDD-2-conclusions Conclusions

In summary, in this tutorial you should have learned how to use PLUMED to:
- Setup and run a metadynamics calculation.
- Compute free energies from the metadynamics bias potential using the \ref sum_hills utility.
- Reweight a metadynamics simulation 

*/

link: @subpage master-ISDD-2

description: This tutorial explains how to use PLUMED to run metadynamics simulations 

additional-files: master-ISDD-2