.. _rmfast:
Removing fastest degrees of freedom
-----------------------------------
The maximum time step in MD simulations is limited by the smallest
oscillation period that can be found in the simulated system.
Bond-stretching vibrations are in their quantum-mechanical ground state
and are therefore better represented by a constraint instead of a
harmonic potential.
For the remaining degrees of freedom, the shortest oscillation period
(as measured from a simulation) is 13 fs for bond-angle vibrations
involving hydrogen atoms. Taking as a guideline that with a Verlet
(leap-frog) integration scheme a minimum of 5 numerical integration
steps should be performed per period of a harmonic oscillation in order
to integrate it with reasonable accuracy, the maximum time step will be
about 3 fs. Disregarding these very fast oscillations of period 13 fs,
the next shortest periods are around 20 fs, which will allow a maximum
time step of about 4 fs.
Removing the bond-angle degrees of freedom from hydrogen atoms can best
be done by defining them as virtual interaction sites instead of normal
atoms. Whereas a normal atom is connected to the molecule with bonds,
angles and dihedrals, a virtual site’s position is calculated from the
position of three nearby heavy atoms in a predefined manner (see also
sec. :ref:`virtualsites`). For the hydrogens in water and in hydroxyl,
sulfhydryl, or amine groups, no degrees of freedom can be removed,
because rotational freedom should be preserved. The only other option
available to slow down these motions is to increase the mass of the
hydrogen atoms at the expense of the mass of the connected heavy atom.
This will increase the moment of inertia of the water molecules and the
hydroxyl, sulfhydryl, or amine groups, without affecting the equilibrium
properties of the system and without affecting the dynamical properties
too much. These constructions will shortly be described in
sec. :ref:`vsitehydro` and have previously been described in full
detail \ :ref:`148 `.
Using both virtual sites and modified masses, the next bottleneck is
likely to be formed by the improper dihedrals (which are used to
preserve planarity or chirality of molecular groups) and the peptide
dihedrals. The peptide dihedral cannot be changed without affecting the
physical behavior of the protein. The improper dihedrals that preserve
planarity mostly deal with aromatic residues. Bonds, angles, and
dihedrals in these residues can also be replaced with somewhat elaborate
virtual site constructions.
All modifications described in this section can be performed using the
|Gromacs| topology building tool :ref:`pdb2gmx `. Separate options exist to
increase hydrogen masses, virtualize all hydrogen atoms, or also
virtualize the aromatic rings in standard residues. **Note** that when all hydrogen atoms
are virtualized, those inside the aromatic residues will be virtualized
as well, *i.e.* hydrogens in the aromatic residues are treated
differently depending on the treatment of the aromatic residues. Note
further that the virtualization of aromatic rings is deprecated.
Parameters for the virtual site constructions for the hydrogen atoms are
inferred from the force-field parameters (*vis*. bond lengths and
angles) directly by :ref:`grompp ` while processing the topology file. The
constructions for the aromatic residues are based on the bond lengths
and angles for the geometry as described in the force fields, but these
parameters are hard-coded into :ref:`pdb2gmx ` due to the complex nature of the
construction needed for a whole aromatic group.
.. _vsitehydro:
Hydrogen bond-angle vibrations
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Construction of virtual sites
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
.. _fig-vsitehydro:
.. figure:: plots/dumtypes.*
:width: 11.00000cm
The different types of virtual site constructions used for hydrogen
atoms. The atoms used in the construction of the virtual site(s) are
depicted as black circles, virtual sites as gray ones. Hydrogens are
smaller than heavy atoms. A: fixed bond angle, note
that here the hydrogen is not a virtual site; B: in
the plane of three atoms, with fixed distance; C: in
the plane of three atoms, with fixed angle and distance;
D: construction for amine groups
(-NH\ :math:`_2` or -NH\ :math:`_3^+`),
see text for details.
The goal of defining hydrogen atoms as virtual sites is to remove all
high-frequency degrees of freedom from them. In some cases, not all
degrees of freedom of a hydrogen atom should be removed, *e.g.* in the
case of hydroxyl or amine groups the rotational freedom of the hydrogen
atom(s) should be preserved. Care should be taken that no unwanted
correlations are introduced by the construction of virtual sites, *e.g.*
bond-angle vibration between the constructing atoms could translate into
hydrogen bond-length vibration. Additionally, since virtual sites are by
definition massless, in order to preserve total system mass, the mass of
each hydrogen atom that is treated as virtual site should be added to
the bonded heavy atom.
Taking into account these considerations, the hydrogen atoms in a
protein naturally fall into several categories, each requiring a
different approach (see also :numref:`Fig. %s `).
- *hydroxyl (-OH) or sulfhydryl (-SH) hydrogen:*
The only internal degree of freedom in a hydroxyl group
that can be constrained is the bending of the C-O-H
angle. This angle is fixed by defining an additional bond of
appropriate length, see :numref:`Fig. %s A`.
Doing so removes the high-frequency angle bending, but leaves the
dihedral rotational freedom. The same goes for a sulfhydryl group.
**Note** that in these cases the hydrogen is not treated as a virtual
site.
- *single amine or amide (-NH-) and aromatic hydrogens
(-CH-):*
The position of these hydrogens cannot be
constructed from a linear combination of bond vectors, because of the
flexibility of the angle between the heavy atoms. Instead, the
hydrogen atom is positioned at a fixed distance from the bonded heavy
atom on a line going through the bonded heavy atom and a point on the
line through both second bonded atoms, see
:numref:`Fig. %s B`.
- *planar amine (-NH*:math:`_2`) *hydrogens:* The method
used for the single amide hydrogen is not well suited for planar
amine groups, because no suitable two heavy atoms can be found to
define the direction of the hydrogen atoms. Instead, the hydrogen is
constructed at a fixed distance from the nitrogen atom, with a fixed
angle to the carbon atom, in the plane defined by one of the other
heavy atoms, see :numref:`Fig. %s C`.
- *amine group (umbrella -NH*:math:`_2` *or
-NH*:math:`_3^+`)* hydrogens:* Amine hydrogens with
rotational freedom cannot be constructed as virtual sites from the
heavy atoms they are connected to, since this would result in loss of
the rotational freedom of the amine group. To preserve the rotational
freedom while removing the hydrogen bond-angle degrees of freedom,
two “dummy masses” are constructed with the same total mass, moment
of inertia (for rotation around the C-N bond) and
center of mass as the amine group. These dummy masses have no
interaction with any other atom, except for the fact that they are
connected to the carbon and to each other, resulting in a rigid
triangle. From these three particles, the positions of the nitrogen
and hydrogen atoms are constructed as linear combinations of the two
carbon-mass vectors and their outer product, resulting in an amine
group with rotational freedom intact, but without other internal
degrees of freedom. See :numref:`Fig. %s D`.
.. figure:: plots/dumaro.*
:width: 15.00000cm
The different types of virtual site constructions used for aromatic
residues. The atoms used in the construction of the virtual site(s)
are depicted as black circles, virtual sites as gray ones. Hydrogens
are smaller than heavy atoms. A: phenylalanine;
B: tyrosine (note that the hydroxyl hydrogen is *not*
a virtual site); C: tryptophan; D:
histidine.
Out-of-plane vibrations in aromatic groups
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
The planar arrangements in the side chains of the aromatic residues
lends itself perfectly to a virtual-site construction, giving a
perfectly planar group without the inherently unstable constraints that
are necessary to keep normal atoms in a plane. The basic approach is to
define three atoms or dummy masses with constraints between them to fix
the geometry and create the rest of the atoms as simple virtual sites
type (see sec. :ref:`virtualsites`) from these three. Each of the
aromatic residues require a different approach:
- *Phenylalanine:* C\ :math:`_\gamma`,
C\ :math:`_{{\epsilon}1}`, and
C\ :math:`_{{\epsilon}2}` are kept as normal atoms,
but with each a mass of one third the total mass of the phenyl group.
See :numref:`Fig. %s A`.
- *Tyrosine:* The ring is treated identically to the phenylalanine
ring. Additionally, constraints are defined between
C\ :math:`_{{\epsilon}1}`,
C\ :math:`_{{\epsilon}2}`, and
O\ :math:`_{\eta}`. The original improper dihedral
angles will keep both triangles (one for the ring and one with
O\ :math:`_{\eta}`) in a plane, but due to the larger
moments of inertia this construction will be much more stable. The
bond-angle in the hydroxyl group will be constrained by a constraint
between C\ :math:`_\gamma` and
H\ :math:`_{\eta}`. **Note** that the hydrogen is not
treated as a virtual site. See
:numref:`Fig. %s B`.
- *Tryptophan:* C\ :math:`_\beta` is kept as a normal
atom and two dummy masses are created at the center of mass of each
of the rings, each with a mass equal to the total mass of the
respective ring (C\ :math:`_{{\delta}2}` and
C\ :math:`_{{\epsilon}2}` are each counted half for
each ring). This keeps the overall center of mass and the moment of
inertia almost (but not quite) equal to what it was. See
:numref:`Fig. %s C`.
- *Histidine:* C\ :math:`_\gamma`,
C\ :math:`_{{\epsilon}1}` and
N\ :math:`_{{\epsilon}2}` are kept as normal atoms,
but with masses redistributed such that the center of mass of the
ring is preserved. See :numref:`Fig. %s D`.