Non-equilibrium pulling
-----------------------
When the distance between two groups is changed continuously, work is
applied to the system, which means that the system is no longer in
equilibrium. Although in the limit of very slow pulling the system is
again in equilibrium, for many systems this limit is not reachable
within reasonable computational time. However, one can use the Jarzynski
relation \ :ref:`135 ` to obtain the equilibrium free-energy difference
:math:`\Delta G` between two distances from many non-equilibrium
simulations:
.. math:: \Delta G_{AB} = -k_BT \log \left\langle e^{-\beta W_{AB}} \right\rangle_A
:label: eqJarz
where :math:`W_{AB}` is the work performed to force the system along
one path from state A to B, the angular bracket denotes averaging over a
canonical ensemble of the initial state A and :math:`\beta=1/k_B T`.
.. _pull:
Collective variables: the pull code
-----------------------------------
The pull code applies forces or constraints on
collective variables (sometimes referred to as reaction coordinates). The basic collective pull coordinates are
a distance, angle and dihedral angle between centers of mass of groups
atoms, the so-called "pull groups". More complex collective variables
can be defined using :ref:`transformationcoord`.
A pull group can be part of one or more pull coordinates.
Furthermore, a coordinate can also operate on a
single group and an absolute reference position in space. The distance
between a pair of groups can be determined in 1, 2 or 3 dimensions, or
can be along a user-defined vector. The reference distance can be
constant or can change linearly with time. Normally all atoms are
weighted by their mass, but an additional weighting factor can also be
used.
.. _fig-pull:
.. figure:: plots/pull.*
:width: 6.00000cm
Schematic picture of pulling a lipid out of a lipid bilayer with
umbrella pulling. :math:`V_{rup}` is the velocity at which the spring
is retracted, :math:`Z_{link}` is the atom to which the spring is
attached and :math:`Z_{spring}` is the location of the spring.
Several different pull types, i.e. ways to apply the pull force, are
supported, and in all cases the reference distance can be constant or
linearly changing with time.
#. **Umbrella pulling** A harmonic potential is applied between the
centers of mass of two groups. Thus, the force is proportional to the
displacement.
#. **Constraint pulling** The distance between the centers of mass of
two groups is constrained. The constraint force can be written to a
file. This method uses the SHAKE algorithm but only needs 1 iteration
to be exact if only two groups are constrained.
#. **Constant force pulling** A constant force is applied between the
centers of mass of two groups. Thus, the potential is linear. In this
case there is no reference distance of pull rate.
#. **Flat bottom pulling** Like umbrella pulling, but the potential and
force are zero for coordinate values below
(``pull-coord?-type = flat-bottom``) or above
(``pull-coord?-type = flat-bottom-high``) a reference
value. This is useful for restraining e.g. the distance between two
molecules to a certain region.
#. **External potential** This takes the potential acting on the reaction
coordinate from another module. Current only the Accelerated Weight
Histogram method (see sec. :doc:`awh`) is supported, which provides
adaptive biasing of pull coordinates.
In addition, there are different types of reaction coordinates,
so-called pull geometries. These are set with the :ref:`mdp`
option ``pull-coord?-geometry``.
Definition of the center of mass
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
In |Gromacs|, there are three ways to define the center of mass of a
group. The standard way is a “plain” center of mass, possibly with
additional weighting factors. With periodic boundary conditions it is no
longer possible to uniquely define the center of mass of a group of
atoms. Therefore, a reference atom is used. For determining the center
of mass, for all other atoms in the group, the closest periodic image to
the reference atom is used. This uniquely defines the center of mass. By
default, the middle (determined by the order in the topology) atom is
used as a reference atom, but the user can also select any other atom if
it would be closer to center of the group.
When there are large pull groups, such as a
lipid bilayer, ``pull-pbc-ref-prev-step-com`` can be used to avoid potential
large movements of the center of mass in case that atoms in the pull group
move so much that the reference atom is too far from the intended center of mass.
With this option enabled the center of mass from the previous step is used,
instead of the position of the reference atom, to determine the reference position.
The position of the reference atom is still used for the first step. For large pull
groups it is important to select a reference atom that is close to the intended
center of mass, i.e. do not use ``pull-group?-pbcatom = 0``.
For a layered system, for instance a lipid bilayer, it may be of
interest to calculate the PMF of a lipid as function of its distance
from the whole bilayer. The whole bilayer can be taken as reference
group in that case, but it might also be of interest to define the
reaction coordinate for the PMF more locally. The :ref:`mdp`
option ``pull-coord?-geometry = cylinder`` does not use all
the atoms of the reference group, but instead dynamically only those
within a cylinder with radius ``pull-cylinder-r`` around the
pull vector going through the pull group. This only works for distances
defined in one dimension, and the cylinder is oriented with its long
axis along this one dimension. To avoid jumps in the pull force,
contributions of atoms are weighted as a function of distance (in
addition to the mass weighting), for atom :math:`i`:
.. math:: \begin{aligned}
w_i(r_i < r_\mathrm{cyl}) & = &
1-2 \left(\frac{r_i}{r_\mathrm{cyl}}\right)^2 + \left(\frac{r_i}{r_\mathrm{cyl}}\right)^4 \\
w_i(r_i \geq r_\mathrm{cyl}) & = & 0\end{aligned}
:label: eqnpulldistmassweight
Note that the radial dependence on the weight causes a radial force on
both cylinder group and the other pull group:
.. math:: \begin{aligned}
F^\mathrm{radial}_i(r_i < r_\mathrm{cyl}) & = &
F^\mathrm{pull} a_i \frac{1}{\sum_i w_i}\frac{4}{r_\mathrm{cyl}^4} r_i (r_i^2 - r_\mathrm{cyl}^2) \\
F^\mathrm{radial}_i(r_i \geq r_\mathrm{cyl}) & = & 0\end{aligned}
:label: eqnpulldistmassweightradialforce
where :math:`F^\mathrm{pull}` is the pull force working between the groups
and :math:`a_i` is the axial distance of atom :math:`i` to the center of
mass of the cylinder group. This is an undesirable,
but unavoidable effect. To minimize this effect, the cylinder radius
should be chosen sufficiently large. The effective mass is 0.47 times
that of a cylinder with uniform weights and equal to the mass of uniform
cylinder of 0.79 times the radius.
.. _fig-pullref:
.. figure:: plots/pullref.*
:width: 6.00000cm
Comparison of a plain center of mass reference group versus a
cylinder reference group applied to interface systems. C is the
reference group. The circles represent the center of mass of two
groups plus the reference group, :math:`d_c` is the reference
distance.
For a group of molecules in a periodic system, a plain reference group
might not be well-defined. An example is a water slab that is connected
periodically in :math:`x` and :math:`y`, but has two liquid-vapor
interfaces along :math:`z`. In such a setup, water molecules can
evaporate from the liquid and they will move through the vapor, through
the periodic boundary, to the other interface. Such a system is
inherently periodic and there is no proper way of defining a “plain”
center of mass along :math:`z`. A proper solution is to using a cosine
shaped weighting profile for all atoms in the reference group. The
profile is a cosine with a single period in the unit cell. Its phase is
optimized to give the maximum sum of weights, including mass weighting.
This provides a unique and continuous reference position that is nearly
identical to the plain center of mass position in case all atoms are all
within a half of the unit-cell length. See ref :ref:`136 `
for details.
When relative weights :math:`w_i` are used during the calculations,
either by supplying weights in the input or due to cylinder geometry or
due to cosine weighting, the weights need to be scaled to conserve
momentum:
.. math:: w'_i = w_i
\left. \sum_{j=1}^N w_j \, m_j \right/ \sum_{j=1}^N w_j^2 \, m_j
:label: eqnpullmassscale
where :math:`m_j` is the mass of atom :math:`j` of the group. The mass
of the group, required for calculating the constraint force, is:
.. math:: M = \sum_{i=1}^N w'_i \, m_i
:label: eqnpullconstraint
The definition of the weighted center of mass is:
.. math:: \mathbf{r}_{com} = \left. \sum_{i=1}^N w'_i \, m_i \, \mathbf{r}_i \right/ M
:label: eqnpullcom
From the centers of mass the AFM, constraint, or umbrella force
:math:`\mathbf{F}_{\!com}` on each group can be
calculated. The force on the center of mass of a group is redistributed
to the atoms as follows:
.. math:: \mathbf{F}_{\!i} = \frac{w'_i \, m_i}{M} \, \mathbf{F}_{\!com}
:label: eqnpullcomforce
Definition of the pull direction
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
The most common setup is to pull along the direction of the vector
containing the two pull groups, this is selected with
``pull-coord?-geometry = distance``. You might want to pull
along a certain vector instead, which is selected with
``pull-coord?-geometry = direction``. But this can cause
unwanted torque forces in the system, unless you pull against a
reference group with (nearly) fixed orientation, e.g. a membrane protein
embedded in a membrane along x/y while pulling along z. If your
reference group does not have a fixed orientation, you should probably
use ``pull-coord?-geometry = direction-relative``, see
:numref:`Fig. %s `. Since the potential now depends
on the coordinates of two additional groups defining the orientation,
the torque forces will work on these two groups.
.. _fig-pulldirrel:
.. figure:: plots/pulldirrel.*
:width: 5.00000cm
The pull setup for geometry ``direction-relative``. The
“normal” pull groups are 1 and 2. Groups 3 and 4 define the pull
direction and thus the direction of the normal pull forces (red).
This leads to reaction forces (blue) on groups 3 and 4, which are
perpendicular to the pull direction. Their magnitude is given by the
“normal” pull force times the ratio of :math:`d_p` and the distance
between groups 3 and 4.
Definition of the angle and dihedral pull geometries
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Four pull groups are required for ``pull-coord?-geometry =
angle``. In the same way as for geometries with two groups, each
consecutive pair of groups :math:`i` and :math:`i+1` define a vector
connecting the COMs of groups :math:`i` and :math:`i+1`. The angle is
defined as the angle between the two resulting vectors. E.g., the
:ref:`mdp` option ``pull-coord?-groups = 1 2 2 4``
defines the angle between the vector from the COM of group 1 to the COM
of group 2 and the vector from the COM of group 2 to the COM of group 4.
The angle takes values in the closed interval [0, 180] deg. For
``pull-coord?-geometry = angle-axis`` the angle is defined
with respect to a reference axis given by
``pull-coord?-vec`` and only two groups need to be given.
The dihedral geometry requires six pull groups. These pair up in the
same way as described above and so define three vectors. The dihedral
angle is defined as the angle between the two planes spanned by the two
first and the two last vectors. Equivalently, the dihedral angle can be
seen as the angle between the first and the third vector when these
vectors are projected onto a plane normal to the second vector (the axis
vector). As an example, consider a dihedral angle involving four groups:
1, 5, 8 and 9. Here, the :ref:`mdp` option
``pull-coord?-groups = 8 1 1 5 5 9`` specifies the three
vectors that define the dihedral angle: the first vector is the COM
distance vector from group 8 to 1, the second vector is the COM distance
vector from group 1 to 5, and the third vector is the COM distance
vector from group 5 to 9. The dihedral angle takes values in the
interval (-180, 180] deg and has periodic boundaries.
.. _transformationcoord:
The transformation pull coordinate
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
The transformation pull coordinate is a "meta" pull coordinate that can
be used to define more complex collective variables.
It can transform one or more other pull coordinates using an arbitrary
mathematical expression. This is a powerful tool for generating
complex collective variables.
A simple example is a contact coordinate using a non-linear transformation
of a distance. More complex examples are a (non-)linear combination of
two or more pull coordinates or a sum of contacts.
Typically, the force constant for pull coordinate(s) the transformation
coordinates acts on should be zero. This avoids
unintended addition of direct forces on the pull coordinate(s)
to the indirect forces from the transition pull coordinate. This is not
a requirement, but having both a direct and indirect, from the tranformation
coordinate, force working on them is almost never desirable.
If the transformation is a linear combination of multiple distances,
it is useful to normalize the coefficients
such that the transformation coordinate also has units of nanometer.
That makes both the choice of the force constant and the interpretation easier.
Here are two examples of pull sections of the :ref:`mdp` input that use
a tranformation coordinate setups. The first is a contact reaction coordinate
that is 1 at contact and 0 at larger distances:
::
pull = yes
pull-ngroups = 2
pull-ncoords = 2
pull-group1-name = groupA
pull-group2-name = groupB
pull-coord1-type = umbrella
pull-coord1-geometry = distance
pull-coord1-groups = 1 2
pull-coord1-dim = Y Y Y
pull-coord1-k = 0 ; avoid forces working directly on this distance
pull-coord2-type = umbrella
pull-coord2-geometry = transformation
pull-coord2-expression = 1/(1 + exp(50*(x1 - 1.8*0.3))) ; x1 refers to the value of coord1
pull-coord2-init = 1 ; this restrains the distance to having the contact
pull-coord2-k = 100
The second example is an average of two distances:
::
pull = yes
pull-ngroups = 4
pull-ncoords = 3
pull-group1-name = groupA
pull-group2-name = groupB
pull-group3-name = groupC
pull-group4-name = groupD
pull-coord1-type = umbrella
pull-coord1-geometry = distance
pull-coord1-groups = 1 2
pull-coord1-dim = Y Y Y
pull-coord1-k = 0 ; avoid forces working directly on this distance
pull-coord2-type = umbrella
pull-coord2-geometry = distance
pull-coord2-groups = 3 4
pull-coord2-dim = Y Y Y
pull-coord2-k = 0 ; avoid forces working directly on this distance
pull-coord3-type = umbrella
pull-coord3-geometry = transformation
pull-coord3-expression = 0.5*(x1 + x2) ; x1 and x2 refer to the value of coord1 and coord2
pull-coord3-init = 0.8 ; restrains the average distance to 0.8 nm
pull-coord3-k = 1000
Limitations
^^^^^^^^^^^
There is one theoretical limitation: strictly speaking, constraint
forces can only be calculated between groups that are not connected by
constraints to the rest of the system. If a group contains part of a
molecule of which the bond lengths are constrained, the pull constraint
and LINCS or SHAKE bond constraint algorithms should be iterated
simultaneously. This is not done in |Gromacs|. This means that for
simulations with ``constraints = all-bonds`` in the :ref:`mdp` file pulling is,
strictly speaking, limited to whole molecules or groups of molecules. In
some cases this limitation can be avoided by using the free energy code,
see sec. :ref:`fepmf`. In practice, the errors caused by not iterating
the two constraint algorithms can be negligible when the pull group
consists of a large amount of atoms and/or the pull force is small. In
such cases, the constraint correction displacement of the pull group is
small compared to the bond lengths.