The life

of molecules

January 14, 2015

Page 1

What is going on at the atomic level?

The life of molecules

Calculating whats going on at the atomic level
Florian Hse and Jose Ramon Villanueva Valencia
Clubes de Ciencia
Guanajuato - Enero 2015

Contents
1 Integration Algorithms
1.1 Principles of Classical Mechanics .
1.2 Numerically calculating forces . . .
1.2.1 Forward Difference method
1.2.2 Central Difference method .
1.3 Euler Algorithm . . . . . . . . . .
1.4 Verlet Algorithm . . . . . . . . . .
1.5 Leap Frog Algorithm . . . . . . . .
1.6 Comparison . . . . . . . . . . . . .

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2 Force Fields
2.1 Important Interactions . . . . . . . . .
2.1.1 Electrostatics . . . . . . . . . .
2.1.2 Magnetostatics . . . . . . . . .
2.1.3 Gravity . . . . . . . . . . . . .
2.1.4 Dispersion interactions . . . . .
2.1.5 Pauli repulsions . . . . . . . . .
2.1.6 Chemical bonds . . . . . . . . .
2.2 Simple Force Field expressions . . . .
2.3 Treatment of non-specific interactions
3 Environmental Controls
3.1 Thermodynamic ensembles .
3.2 Boundary Conditions . . . . .
3.3 Heat bath . . . . . . . . . . .
3.3.1 Andersen thermostat .
3.3.2 Berendsen thermostat
3.3.3 Extended Nose-Hoover
3.4 Pressure control . . . . . . . .
3.4.1 Berendsen barostat . .
3.4.2 Andersen barostat . .

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thermostat
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4 Principles of diffusion

26

5 Bash commands

27

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 2

1 Integration Algorithms
The key element of every Molecular Dynamics Engine is a stable integration algorithm that
accounts for correct time propagation of the system. As typical MD simulations propagate a
system for about 2 fs per step but simulation times of the order of 1 s shall be achieved, the
error per step must be very small to assure simulating a physically correct behavior.

1.1 Principles of Classical Mechanics

The first thing to think about when trying to compute the behavior of many particle systems
is how to propagate the system in time. For the following considerations we assume we would
have some magical black box method that provides us with the potential every single particle
feels. Additionally we want to assume that the particles behave classically, thus neither special relativity nor quantum mechanics need to be taken into account when propagating the
system in time.
Having knowledge about the potential at the position of a particle as well as the close surrounding allows for calculating the effective force acting on the particle. Assuming the many
particles system consists of N particles, each having coordinates and velocities of


xi
v xi
r i = yi
and
v i = v yi
zi
v zi
where i is an index indicating the ith particle the effective force on the ith particle F~i (~r) can
be calculated via the negative gradient of the potential

x U
Fxi
U (r i )
~ (r i )
Fyi = y U
F i (r i ) =
= U
r i
Fzi
z U
Having computed the forces on the ith particle Newtons second law can be used to calculate
the acceleration of the particle caused by the potential. In order to do so the inertial mass of
the particle is needed as a parameter of the model.


Fxi
axi
Fyi = mi ayi
F i (r i ) = mi ai (r i )
Fzi
azi
Acceleration is defined as the rate with which velocity changes over time. Additionally, velocity
is the rate with which the position changes over time. Hence, acceleration is the second total
derivative of position with respect to time. With this relation, the change in position of a
particle can be related to the potential the particles feels at a given time t which allows for
estimating the particles position at time t + t.
d2
1
1 U (~ri )
ri =
F i (r i ) =
2
dt
mi
mi ri
Then only thing we still need to think about is how to integrate this equation of motion
efficiently. This is what integration algorithms can be used for.

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 3

1.2 Numerically calculating forces

Before we start thinking about integration algorithms to propagate the system in time we will
try to numerically calculate the spacial derivative of the potential to obtain the forces. For
simplicity we well consider this problem first in only one dimension and later generalize it to
three dimensions.
1.2.1 Forward Difference method
A very simple method to numerically calculate derivatives can be developed by considering
the formal definition of the first derivative f 0 (x) of a given function f : x 7 f (x). The first
derivative of f at position x = a is defined as
f (a + h) f (a)
h0
h

f 0 (a) = lim

This expression is also called Differential Quotient. Instead of calculating the Differential
Quotient, the forward difference method approximates the first derivative by only computing
the Difference Quotient
Definition 1
Given an arbitrary function f : x 7 f (x), the forward difference first deriva0
tive fFD at a given position x = a is given by
0
fFD
(a) =

f (a + h) f (a)
h

for some constant h > m , where m is the machine precision of the machine used for the
computation.
Of course this approximation of the first derivative yields a certain error. The error can be
estimated by Taylor expanding the expression for the forward difference derivative
0
fFD
(x) =

f (x + h) f (x)
f (x) + hf 0 (x) + (h2 /2) f 00 (x) + . . . f (x)
=
h
h
0
00
= f (x) + (h/2) f (x) + . . .

For small h the error in this approximation is mostly determined by h itself and the second
derivative of the considered function. Assuming that the function is well-behaved, meaning
that it is sufficiently smooth, every derivative to any order is of about the same order of
magnitude as the function itself. Thus, we may conclude that the error is mostly determined
by the choice of h.
The trade-off in this method as in most of the methods for calculating first derivatives is that
on one hand h cannot be chosen arbitrarily small as we need to be significantly above the
machine precision but on the other hand h should be small enough to sufficiently decrease the
error in the computation.
It can be shown that for double precision the minimum error being the sum of the round-off
error and the approximation error of 3 108 is achieved for h 4 108

The life
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What is going on at the atomic level?

January 14, 2015

Page 4

1.2.2 Central Difference method

The previously discussed forward difference method for approximating the first derivative of a
function can be improved by not considering a given function f at the position the derivative
should be calculated at and the value of the function in some arbitrary distance h from this
point but rather taking into account the surrounding of this function f around position a.
This idea is depicted in figure 1. As opposed to the forward difference derivative, the central
difference derivative is defined as
Definition 2
Given an arbitrary function f : x 7 f (x), the central difference first deriva0
tive fCD
at a given position x = a is given by
0
fCD
(a) =

f (a + h/2) f (a h/2)
h

for some constant h > m , where m is the machine precision of the machine used for the
computation.
It can be shown that the error made by this method is significantly smaller than the error
of the forward difference method. In order to do so the defining expression is again Taylor
expanded
0
(x) =
fCD

f (x + h/2) f (x h/2)
h
2
h 0
f (x) + 2 f (x) + h8 f 00 (x) +

h3 (3)
(x)
48 f

+ . . . f (x) + h2 f 0 (x)
h

h2 00
8 f (x)

h3 (3)
(x)
48 f

...

= f 0 (x) + (h2 /24) f (3) (x) + . . .

Again, following the argument that any arbitrary derivative of the function should be of about
the same order of magnitude the error if this method is in the order of h2 , which is expected
to be much smaller than h for small h. It turns out that the minimum error of this method,
being the sum of the round-off error and the approximation error, is about 3 1011 and
can be achieved for h = 3 105 .
Having derived two different methods for calculating the first derivative of a given function
at a given position, the central difference method provides already quite good results. There
are many other methods with even higher accuracy like the extrapolated difference method
but these methods typically require more potential evaluations. Since potential evaluations
are the bottleneck of MD simulations we want to maintain as few potential evaluations as
possible. Hence, we will stick with the central difference method in our application.

1.3 Euler Algorithm

Knowing how to calculate forces and thus accelerations on a particular particle given the
potential in a small surrounding of the particle we are, in principle, able to solve Newtons
equation of motion. However, doing this numerically yields some challenges that need to be
overcome.
In order to fully describe one particle in phase space both its position and its momentum
has to be known. Thus, any algorithm should be capable of computing both position and
momenta for future times. The position r(t + t) and velocity v(t + t) of a particle at some

The life
of molecules

January 14, 2015

Page 5

What is going on at the atomic level?

(A):

(B):
f (x)

f (x)

f (x)

f (x)

f 0 (a)

f 0 (a)

0 (a)
fCD

0 (a)
fFD

a a+h

a h/2

a a + h/2

Figure 1: Derivative Methods: Depicted are the basic ideas behind the forward difference
method (A) and the central difference method (B). Both can be used to approximate
the first derivative of a given function but based on the definition of the methods the
central difference method performs significantly better than the forward difference
method even though the number of evaluations is the same.
time t + t can be calculated from the previous phase space point (r, v)(t) by simply Taylor
expanding the expressions for later times.
dr(t) 1
d2 r
+ (t)2 2 + . . .
dt
2
d t
dv(t)
v(t + t) = v(t) + t
+ ...
dt
r(t + t) = r(t) + t

Note that truncating the sums after any arbitrary order of t is exact for infinitesimal t. The
occurring derivatives can be computed from the underlying physics
dr(t)
= v(t)
dt

d2 r(t)
dv(t)
F (t)
=
= a(t) =
2
dt
dt
m

where F (t) are the forces acting on the particle at time t. A numerical way to calculate the
next position and velocity is now to consider a finite t t but still truncate the sums
of the Taylor expansion. This way a certain error is made, that is smaller the smaller t is
chosen. However, in order to achieve interesting time scales within a reasonable simulation
time t should not be chosen too small.
Given the position r N and velocity v N at step N of the simulation, position and velocities
can be updated via the following scheme
Definition 3

Euler Algorithm
r N +1 = r N + tv N +
v N +1 = v N + t

(t)2 F N
2
m

FN
m

Note that effectively there is only one force evaluation required for this integration algorithm.
Nevertheless, the error made by this algorithm in the position of the particle if of the order
of (t)3 as this is the first order that was neglected in the Taylor expansion.

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 6

The here presented Euler method is known to be a quite inaccurate integration algorithm
and should only be used as an academic example. Even though the Euler method can be
comparably fast, this algorithm is rather unstable.

1.4 Verlet Algorithm

A more sophisticated method than the Euler Algorithm is the Verlet Algorithm. Similar to
computing the first derivative with the central difference method the Verlet Algorithm does
not only calculate the next position by making use of the current position but rather of the
current and the previous location of the particle. By including more information into the
calculation the algorithm becomes more stable and the error decreases. A formal derivation
of the Verlet Algorithm might look as follows. We consider the position of the particle r at
time t + t and t t and Taylor expand both expressions.
3
dr(t) 1
d2 r(t) 1
3 d r(t)
+ (t)2
+
(t)
+ ...
dt
2
dt2
6
dt3
3
dr(t) 1
d2 r(t) 1
3 d r(t)

+ ...
r(t t) = r t
+ (t)2
(t)
dt
2
dt2
6
dt3

r(t + t) = r + t

Both expressions can now be added and slightly rearranged, which leads to
r(t + t) = 2r(t) r(t t) + (t)2

d2 r(t)
+ ...
dt2

Again, note that truncating the sum at any arbitrary order of t still yields a true equation
for infinitesimal t. However, for numerical simulations a finite t t is required. By
considering the current and the previous position of the particular an equation could be
derived, which is exact up to terms of (t)4 , which is already an order of magnitude better
than the Euler Algorithm.
Substituting the second time derivative of the position with the underlying physics the Verlet
Algorithm can be effectively used to determine the position r N +1 of a particle at step N + 1
of a simulation.
Definition 4

Verlet Algorithm
r N +1 = 2r N r N 1 + (t)2

FN
m

Note that the Verlet algorithm does not explicitly include velocities. However, velocities can
be calculated using the basic idea of the central difference method
r(t + t) r(t) + tv(t)

r(t t) r(t) tv(t)

Subtracting the two equations and rearranging the expression leads to

v(t) =

r(t + t) r(t t)
2t

vN =

r N +1 r N 1
2t

which allows for subsequent computation of the velocities up to an error of (t)2 being very
important for thermodynamically controlling the system as we will see later on.

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 7

1.5 Leap Frog Algorithm

In contrast to the Euler Algorithm which propagates positions and velocities one the same
time discretization and opposed to the Verlet Algorithm which does not explicitly include
velocities at all the Leap Frog Algorithm combines advantages of both previously discussed
methods, namely explicitly calculating velocities as well as an error of (t)3 in the positions.
The basic idea behind the Leap Frog algorithm is to propagate positions and velocities not
at the same points in time but rather along time points which are shifted by t. The mathematical reasoning behind this idea are widely used midpoint rules which were successfully
applied to many problems such as numerical integration. Hence, in correspondence to the
equations of the Euler Algorithm the Leap Frog Algorithm follows the basic scheme of
r(t + t) = r(t) + v(t + t/2)t
F (t + t)
v(t + 3t/2) = v(t + t/2) +
t
m
In order to calculate the velocities at times t + nt with n being a natural number, one can
perform a half step integration
1 F (t)
2 m
1 F (t + t)
v(t + 3t/2) = v(t + t) +
2
m
v(t + t/2) = v(t) +

Using these two equations the Leap Frog algorithm can be formulated in the following way
Definition 5

Leap Frog Algorithm

r N +1 = r N + v N t +
v N +1 = v N +

(t)2 F N
2
m

t
[F N + F N +1 ]
2m

Note that even though the force appears to be evaluated twice during one iteration the number of force evaluation reduces to one by storing the previously calculated results. Hence, the
Leap Frog Algorithm provides also only one force evaluation.
In addition it can be shown that the Leap Frog Algorithm performs a symplectic integration,
meaning that phase space volumes are conserved by this algorithm. This feature arises from
the fact, that the algorithm propagates positions and velocities on independent time grids.
As the Hamiltonian of a single particle consists of one momentum dependent kinetic term and
one position dependent potential term, the total energy does not change when propagating a
system with this algorithm. Having this inbuilt feature of energy conservation we are already
capable of simulating many particle systems in the microcanonical ensemble.

1.6 Comparison
Aside from the already discussed numerical integration techniques there are many more integration algorithms that for example include higher orders in the Taylor expansion or show

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 8

better energy conservation behavior so that larger time steps are possible. However, these
techniques often include more force evaluations which might slow down the speed of the simulation significantly.
The main features a suitable simulation algorithm should have are
simplecticity
few force evaluations
high accuracy
high speed
time reversibility
The Leap Frog integration algorithm comes along with all these features and is thus one of
the most commonly used integration algorithms in Molecular Dynamics engines.
(A):
y

(B):
y

Euler

Verlet

Figure 2: Integration Algorithms: Depicted are the basic principles of simple integration
algorithms. The Euler Algorithm (A) only takes into account information about
the previous position as well as the slope at the current position while the Verlet
Algorithm (B) uses more information and thus stays closer to the actual trajectory
(black).

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 9

2 Force Fields
Considering a many particle system with interacting particles, the interactions between the
particles have to be modelled sufficiently accurate to assure correct simulation of the behavior of the system. However, to keep the algorithms simple and the parameter space small,
only important interactions shall be included into the model. In order to identify relevant
interactions in biological systems the order of magnitude of certain interactions in the regime
biomolecules exist in will be estimated first to then neglect interactions that are sufficiently
weak compared to others. Based on these considerations, an analytical expression for the
potential energy of a many particle system will be derived.

2.1 Important Interactions

In the following we want to investigate the order of magnitude of particular interactions among
particles in a biological many particle system as well as interactions between these particles
and their surrounding environment.
Before actually calculating typical forces caused by prevalent interactions in biological systems
we should think about how to define strong and weak forces. In order to do so a measurement
to which the forces can be compared to is required. Since biological systems exist at rather
constant temperatures of the order of 300 K the canonical ensemble is well suited to describe
the thermodynamics of biological systems. Being in the canonical ensemble the system is
coupled to a heat bath while energy between the heat bath and the system can constantly be
exchanged. The relevant thermal energy is
Etherm = 1kB T 4.144 pN nm
The size of one atom is typically about 1 = 0.1 nm. Biological relevant proteins and other
biomolecules usually consist of more than 1000 atoms which allows for taking 1 nm as the
characteristic length of biomolecules. As the system is coupled to a heat bath with a temperature of 300 K relevant forces must be at least in the order of a few Piconewton. Forces
less than 1 pN are usually to weak to cause any actions while forces stronger than 1 pN might
influence the system.
This consideration allows for estimating whether or not certain forces caused by particular
interactions should be taken into account when modelling the interactions relevant for simulating biomolecules.
2.1.1 Electrostatics
Biomolecules such as proteins and DNA can, in principle, carry a charge. Aside from that,
also within a biomolecule charge distributions are present. For example, there are positively
and negatively charged amino acids and the phosphate in the backbone of DNA are negatively
charged as well.
Maxwells equations tell us that charges cause an electric field which again affects surrounding
charges. The electric field comes along with a potential so that charges in the potential have
some potential energy which might influence the movement of the charges.

The life
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January 14, 2015

Page 10

The force of a charge qi in the electric field Ej caused by another charge qj follows the simple
relation
F = qi Ej
Modelling the charge qj as a point charge1 the electric field and thus the force can be expressed
as follows
Ej =

qj
2
4rij

F =

qi qj
2
4rij

Considering the negatively charged phosphates in the backbone of DNA as an example, the
distance between the charges rij is about 2 nm while each phosphate carries one elementary
charge. Given these numbers, the force between the two phosphates is of the order of
Felect 7 pN
Here we see, that this force is well within the order of magnitude of forces that should be taken
into account. Hence, electrostatic interactions are indeed important to model the behavior of
biomolecules.
2.1.2 Magnetostatics
Nuclei in general carry a magnetic moment in addition to their electric moment. The nuclei with the greatest magnetic moment are protons, which are present in large number in
biomolecules due to the large amount of hydrogen of which biomolecules comprise. Opposed to
the electrostatic scenario, a magnetic moment B in the magnetic field B of another magnetic
moment feel a torque acting on them. The torque depends on both the magnetic moment
and the magnetic field and can be expressed as the product of a force F and a corresponding
lever arm r.
M = B B = F r
Considering the magnetic moment of a proton B = 1.4 1026 Nm/T and a lever arm of
10 nm, the resulting force in a super-strong 1 T magnetic field is
Fmagnet 1.4 107 pN
Magnetic fields are usually weaker than the considered one and the force even with such a
strong magnetic field is much smaller than forces which are relevant for biological systems.
Hence, magnetic interactions do not need to be modelled in a Molecular Dynamics simulation.

This assumption is not too bad because the diameter of the nuclei negligibly small compared to Bohrs
radius.

10

The life
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January 14, 2015

Page 11

2.1.3 Gravity
Considering the forces on particles caused by gravity we need the typical mass of one of the
particles. Considering an entire protein, typically consisting of about 300 amino acids, we
arrive at a typical mass of about
mprotein,typical 60 1021 g
This mass already appears to be quite small. Furthermore, making the (very accurate) assumption that the gravitational potential for proteins on earth does not change along the size
of the protein, the force acting on the entire protein is of the order of
Fgravitational,typical = mprotein,typical g 6 1010 pN
where g = 9.81 ms2 is the gravitational acceleration. Since gravitational forces are much
smaller than the relevant force scale gravity can be neglected in any Molecular Dynamics
simulation.
2.1.4 Dispersion interactions
Dispersion forces are intramolecular forces arising from quantum-induces spontaneous polarization multipoles in molecules. A simple (but not accurate) picture of these types of
interactions is to think about two atoms with their electron clouds around their nuclei (compare figure 3). Assuming the existance of fluctuations, one electron cloud of one atom might
deviate such that the charge centers of positive and negative charges no longer coincide. Thus,
a dipole was created2 . The other atom is now located in the electric field of a dipole. As the
electron cloud and the nucleus react differently to the just arisen dipole the charge centers of
the other atom also separate creating another dipole.
Eventually there are two dipoles interacting through their electric fields. This classical picture allows for correct modelling of the spacial dependence of this interaction even though
a quantum mechanical description might be more appropriate in this case as it respects the
finite number of electrons and the wave nature of the electrons.
Nevertheless, both descriptions predict a potential energy in the form of
Edisp =

3 IA IB A B
2 IA + IB R6

Here, I indicates the first ionization potentials of the atoms and their dipole polarizabilities.
Note that this interaction is attractive due to the minus sign and that the spacial dependence
goes as r6 .
Dispersion relations are the reason why non-polar molecules stick together even though separated states would be favored entropically. Hence, the assumption that dispersion relations
play an important role for biomolecules seems valid.

Considering the finite number of electrons around a nucleus even higher order multipoles can easily be
created but higher order multipoles are typically weaker than dipoles so that they are neglected in this
case.

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A:

B:

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C:

Figure 3: Dispersion Interaction: Depicted is a classical picture of the dispersion interaction between two atoms. Nuclei are shown in red while electron clouds are shown
in blue. Usually, charge centers coincide (A), but due to fluctuations charge centers
might deviate from one another creating a dipole (B). While these fluctuations are
usually short lived for isolated atoms the just formed dipole can induce the creation
of another dipole in another atom as positive and negative charges react differently
to an electric field (C). A system of two induced dipoles has a much longer life time
than a dipole induced by fluctuations alone.
2.1.5 Pauli repulsions
Taking into account the quantum mechanical nature of electrons and nuclei, another interaction arises from a very fundamental quantum mechanics principle, the Pauli exclusion
principle. This principle basically states that two identical fermions3 cannot under any circumstances occupy the same quantum state.
Electrons are particles with spin 1/2 and thus fermions. The quantum state of an electron
in an atom is defined by the orbital the electron occupies and its spin. Due to the Pauli
principle, electrons can only occupy the same orbital if they have different spins. Since the
only spin states that are allowed for the electron are +1/2 and 1/2 there can only be two
electrons per orbital.
One important consequence of this principle is that atoms cannot come arbitrarily close to
one another. Since orbitals occupy a certain space around the nuclei the orbitals of two atoms
start to overlap if they get closer and closer. However, electrons with the same spin cannot
occupy the same orbital and thus be in the same space region. This results in an effective
repulsion.
There is no closed expression for this type of repulsion. However, some characteristics of this
repulsion are known. The repulsion appears on a small length scale but is very strong4 . One
popular mathematical expression used to model this phenomenon is an energy penalty term
of the following form
Eexcl =

K
r12

where K is some arbitrary constant. Other methods model the Pauli repulsion with exponential functions or just a hard wall.
2.1.6 Chemical bonds
In biomolecules, many chemical bonds are present. As biomolecules mostly consist of carbon,
oxygen, nitrogen, hydrogen, phosphate and sulphur, the chemical bonds are mostly either
3
4

Fermions are particles which carry a half-integer spin

In fact, the repulsion is infinitely strong as the Pauli principle is an exclusion principle.

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covalent or non-covalent bonds. These types of bonds are characterized by particular energy
landscapes that can only be calculated quantum mechanically. Analytical solutions to these
problems can only be found for the H2 molecule, all other bonds can only be calculated
approximately by very sophisticated quantum mechanical techniques.
However, all energy landscapes describing chemical bonds between particular atom types have
in common that they are close to the minimum well approximated by a parabola. This idea
arises from the Taylor expansion. Considering any energy landscape E(x) along a reaction
coordinate x and Taylor expanding it around a local minimum x0 yields
E(x0 + x) = E(x0 ) + x

dE(x0 ) 1
d2 E(x0 )
+ (x)2
+ ...
dx2
| dx
{z } 2
=0

Carrying out the quantum mechanical calculations and computing the energy landscapes
suggests that the thermal energy present in biological systems is not sufficient to highly
excite chemical bonds. Thus, expected deviations from the local minimum are rather small,
indicating that the performed Taylor expansion is a good approximation in the considered
regime. Chemical bonds are therefore modelled with an harmonic potential which allows for
the analogy of connecting the atoms via springs.
In addition to the harmonic spring between two adjacent atoms also higher order interactions
need to be modelled. Since orbitals are not necessarily symmetrically distributed around
the nucleus spacial orientations have to be taken into account. This results in preferred
geometrical angles in three atom interactions as well as in preferred dihedral angles in four
atom interactions which influence the resulting geometry of the biomolecule enormously. The
basic idea behind these quantum mechanical effects is depicted in figure ??.
Similar to the energy term for the bond length between two atoms there is also a particular

r0
Figure 4: Orbital Geometry: When two atoms approach each other their orbitals (blue) can
fuse to form bonding and non-bonding orbitals. Orbitals in general occupy certain
space regions as indicated here. Due to the particular geometric distribution of
the orbitals certain conformations are highly preferred by the molecule compared
to others. It can be shown that there is an optimal bond length r0 as well as an
optimal angle 0 for two and three particle systems. Not shown are dihedral angles,
which are defined in four particle interactions.
energy landscape for the angle between three atoms. If calculating the optimal bond length is
already quite challenging, calculating the optimal angle is even harder. Nevertheless it can be
assumed that there exists one optimal angle 0 and that thermal excitations at temperatures

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of 300 K do not change this angle drastically. Taylor expansion of the (unknown) energy
landscape yields
E(0 + ) = E(0 ) +

dE(0 1
d2 E(0 )
+ ()2
+ ...
d
2
d
| {z }
=0

Truncating the sum again allows for modelling the angular potential by a harmonic spring.
In addition due to the three dimensional nature of orbitals there is also another term that
needs to be added for four particle interactions which accounts for the dihedral angle between
the four particles. As this term arises from the repulsion of orbitals there is not only but local
energy minimum but many of them. The dihedral angle energy is most commonly modelled
via
X
k (1 + cos(n 0 ))
E() =
n

Note that this term is rather empirical.

2.2 Simple Force Field expressions

The prior estimates and approximations of prevalent interactions relevant for biological systems now allow for the derivation of an analytical expression which aims to accurately model
the physics underlying the dynamics of molecules. In general, interactions can be divided into
specific interactions and non-specific interactions. Specific interactions occur between atoms
of the molecule that are sequentially close to one another and have chemical bonds established. Non-specific interactions however potentially occur between all atoms in the system
even though they are typically larger if the distance between the considered atoms is small.
Coulombic interactions, dispersion interactions and interactions caused by the Pauli exclusion
principle are among non-specific interactions. To correctly model higher multipole interactions, atoms are typically assigned a partial charge corresponding the electron distribution
around the atoms. Dispersion interactions and repulsions are often consolidated to the so
called Lennard-Jones Potential
 

12  6
VLJ (r) = 4

r
r
where r is the distance between the particles and and are parameters defining the position
and the depth of the minimum.
Combining all relevant interactions into one potential energy term V leads to
X
X
X
V =
kbond (r r0 )2 +
kangle ( 0 )2 +
kdihedral (1 + cos(n 0 ))
bonds

X
charges

angles

qi qj
+
4r

X
particles

 
12
r

dihedrals

 6 
r

This expression captures the most basic features of Molecular Dynamics even though there
are already many parameters included. The parameters can either be obtained directly from
experiments or by trying to fit thermodynamic predictions of Molecular Dynamics Simulation
to experimental results and correcting for the parameters in the MD model.

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Additionally, there are endeavors to improve force fields by taking into account more com-

LJ, Coulomb

Figure 5: Molecular Dynamics Force Field: A simple version of a Molecular Dynamics

Force Field consists of specific interactions (red) and non-specific interactions (orange). Specific interactions are those that try to mimic the physics of chemical
bonds while non-specific interactions arise from general electrostatic and quantum
mechanical principles.
plicated interactions. For examples, some force fields allow for changes in the polarization of
molecules.

2.3 Treatment of non-specific interactions

Even though non-specific interactions can be well modelled by the previously derived expressions there is one computational problem arising from the nature of non-specific interactions.
Considering typical biomolecule of about 10000 atoms there are many interactions to calculate
during one force evaluation.
In the case of the Lennard-Jones potentials however we deal with a quickly decaying potential
(VLJ r6 ). This seduces to only consider spatially close atoms for calculating the force
caused by the Lennard-Jones potentials of other atoms as on one hand atoms far away do
not significantly contribute to the total potential and moreover the change in the potential
a large distances is very small and can be neglected. Considering the overall shape of the
Lennard-Jones potential of a carbon atom (compare figure 6) it can be deduced that a save
cut-off distance is larger than about 10 . Studies have shown that smaller cut-offs produce
artefacts in the simulation.
Instead of simply truncating the potential a slightly more sophisticated method is to shift
the potential at a defined shift distance to a potential that decays to zero in within a finite
distance. Note that the shifting should be smooth and differentiable to avoid artefacts.
The case of the Coulomb potential however is slightly more complicated as the decaying
power is much smaller (VCoulomb r1 ). Nevertheless, cut-offs are considered a fast method
to model Coulomb interactions. Typically cut-off distances are chosen slightly larger (12 )

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A:

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B:

V [ ]

V [ q]

0.2

0.2

0.5

1.0

1.5

2.0

2.5

3.0

0.4

0.6

0.8

1.0

r [ 1/ ( 4 ) ]

r [ ]

-2
- 0.2

-4
- 0.4

-6

- 0.6

- 0.8

-8

- 1.0

- 10

Figure 6: Non-specific interactions: Depicted are the general shapes of the Lennard-Jones
potential (A) and the Coulomb potential (B) in natural units. While the LennardJones potential quickly decays for long distances the Coulomb potential decays much
slower making it necessary to introduce larger cut-offs for the Coulomb potential or
treat coulombic interactions with the Particle Mesh Ewald method.
than van der Waals cut-offs.
But there is a method that allows for a more accurate computation of the Coulomb interactions. This method is called the Particle Mesh Ewald and works particularly well together
with periodic boundary conditions. The general idea of this method is to split potential contributions into short range and long range contributions. While short range contributions
quickly converge in real space, long range contributions quickly converge in Fourier space.
By Fourier transforming the system5 the long range contribution can be calculated efficiently.
Nevertheless there are currently ongoing debates whether or not PME artificially constraints
the system to rather crystal-like conformations as due to the finite simulation box size there
is some (small) area around the origin in Fourier space that does not correspond to the simulated system.
In addition to these techniques for potential computation treatment simulations can further
be sped up by introducing the concept of neighbor lists. To reduce the error of the integration
algorithm typical time steps chosen for the algorithm are in the order of 2 fs. Given this small
time step atoms will not move far for a small amount of integration steps. Having identified
the particles which only weakly interact with the considered particle and thus were neglected
it can be assumed that those particles can also be neglected for the following integration step.
The list of the particles which need to be considered for the evaluation of the potential is
called neighbor list. Depending on the particles simulated neighbor lists are typically updated
every 10 to 100 steps. Note that this parameter should be defined with care.

Note that there are Fast Fourier Transform algorithm which scales as N log N .

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Figure 7: Neighbor Lists: Whenever the force on one particular particle (red) needs to be
calculated, certain cut-offs can be applied to reduce the cost of the force evaluation. The contribution of particles within a specified cut-off (green) is taken into
account while all others are ignored for the force evaluation. However, calculating
distances between particles is costly and scales badly ( N 2 ) so that a neighbor
list is defined containing all particles that are within the force evaluation cut-off
(green) and particles which might enter this zone as long as the neighbor list is not
updated (yellow). Applying this method distances between all atoms only need to
be calculated for every update of the neighbor list.

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3 Environmental Controls
Having a symplectic integration algorithm and a force field describing the potential energy of
the system still does not allow for correct modelling of the dynamics of the biomolecule. First
of all biomolecules experience constant temperature and pressure as they are coupled to the
environment and can exchange energy.
Additionally, in most applications biomolecules exist in aqueous solution. Water is rather
strong dipole and various examples have been found where certain processes only occur due
to the presence of a single water molecule. Aside from the water molecules also ions can have
a huge impact on the behavior of the system. For example in the case of DNA many negative
charges due to the backbone phosphates exist in the system. However, diffusion in real system
allows for local neutralization so that both, water molecules and ions have to be added to the
system to simulate biological relevant dynamics. Coupling the system to temperature and
pressure controls however is slightly more challenging than just adding more molecules to the
system.
Furthermore, in order to simulate the system at either constant volume or constant pressure
boundaries need to be defined. Introducing walls to keep the particles within a specific volume
causes undesired artefacts: As particles will be reflected by the wall, the density of particles
of the same species will be smaller close to the wall compared to the bulk.
How to find solutions to all of the mentioned problems will be discussed in the following
chapter after a short introduction into thermodynamic ensembles.

3.1 Thermodynamic ensembles

In thermodynamics, a state is defined by its thermodynamic variables. A thermodynamics
ensemble is the set of all thermodynamic states a system could possibly be in. Hence, the
thermodynamic ensemble can be considered the probability distribution for a given system.
Depending on environmental influences some thermodynamic quantities might be fixed due
to coupling a bath which can influence thermodynamic quantities of the system.
Considering a system of finite size V containing N particles without being coupled to any
bath, the total energy E of the system will remain constant6 . This ensemble is called the
microcanonical ensemble. Assuming that each state of total energy E is equally likely the
phase space density N V E (r N , pN ) of the ensemble is given by
N V E (r N , pN ) (H(r N , pN ) E)
The total energy is the corresponding thermodynamic potential to this ensemble. Provided a
symplectic integration algorithm a Molecular Dynamics simulation takes place in the microcanonical ensemble. However, this is not always desired.
Biological relevant systems often-times exist at constant temperature. Thus, to closely resemble realistic dynamics of the system it needs to be coupled to a heat bath keeping the
temperature at a constant value. By regulating the temperature the total energy of the system no longer is constant as the heat bath either withdraws energy (if particles are slowed
down) or puts energy into the system (if particles are sped up). The corresponding thermo-

This is a consequence of the first law of thermodynamics.

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dynamic ensemble is called the canonical ensemble with the Helmholtz free energy A as
the appropriate thermodynamic potential. The change in free energy is given by
dA = SdT pdV + dN
which can be derived by Legendre transforming the total energy with respect to temperature.
Since in this ensemble volume, temperature and number of particles does not change the
Helmholtz free energy fully characterizes one particular state and is therefore well suited to
distinguish different states. For this example it can be relatively easy shown that the states
are no longer equally distributed but rather follow a probability distribution N V T (r N , pN )
which weighs the energies in a so-called Boltzmann factor
N

3N

N V T (r , p ) = N !h

eH(r ,p )
dr N dpN eH(rN ,pN )

Here, the factor N !h3N acts as a normalization factor. While N ! can be understood from the
indistinguishableness of the particles, h3N is a normalization factor for the volume of phase
space. Quantum statistical analyses are required to show that this normalization factor is
identical to Plancks constant.
Aside from temperature also pressure is often controlled. In order to also impose a pressure
control to the system the pressure is measured during the simulation and the volume adapted
accordingly. The corresponding ensemble is the isothermal-isobaric ensemble and well
described by the Gibbs free energy G
dG = SdT + V dp + dN
which is derived from the Helmholtz free energy through a Legendre transform with respect to
the volume. As temperature, pressure and number of particles are constant in this ensemble,
the Gibbs free energy can be used as a measure to distinguish states.

3.2 Boundary Conditions

For simulating a system in a particular thermodynamic ensemble certain thermodynamic
variables need to be fixed in the simulations. Considering the canonical variable pressure p
and volume V either of these need to be kept constant for any thermodynamic ensemble. In
order to impose a desired pressure or volume to the system, volume needs to be defined first.
In order to do so, various methods are possible in principle.
One could use fixed boundary conditions, meaning that the considered volume is enclosed
by rigid walls which reflects particles in a mirror-like fashion. This boundary condition is
relatively easy to implement. However, due to the interaction of the wall with the particles7
the system is influenced by the wall. As particles are reflected by the wall the average particle
density in close proximity to the wall significantly drops. Having a smaller probability of
presence (r) close to the walls results in an effective potential Gvirt (r) of the form
Gvirt (r) = kB T ln (r)

For reflecting the particle the wall exerts twice the momentum the particle has perpendicular to the wall
plane to the particle

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Figure 8: Periodic boundary conditions: Depicted is the set-up of a small DNA strand
in aqueous solution with periodic boundary conditions. Due to the boundary conditions, particles at the periphery of the simulation box are not only affected by
potentials caused by close-by atoms but also by potentials caused by periodically
close atoms. Hence, the effective potential a particle feels is the potential caused by
the system and a mirror image of the system. Effectively, the system is replicated
throughout space as depicted.
which repels particles not only at the exact position of the walls but also in close proximity.
In order to make sure that this potential does not affect the molecules of interest a sufficiently
thick layer of solvent molecules is needed that separates the molecule of interest from the wall.
Diffusion processes of the molecule of interest complicate the simulation procedure.
These undesired effects can be avoided by imposing periodic boundary conditions. When
using periodic boundary conditions, the simulated system is virtually replicated beyond the
walls. Molecules that would leave the simulation box enter at the other side. Strictly speaking
there is no box but only a huge space with the same system over and over again (compare
figure 8). Even though periodic boundary conditions to not introduce virtual potentials to
the system there are some complications. The molecule of interest might interact with its
mirror image. Hence, a sufficiently thick (but much thinner compared to rigid walls) layer of
solvent molecules is needed to separate the molecule from its replica.

3.3 Heat bath

In order to achieve constant temperature during a Molecular Dynamics the simulated system
needs to be coupled to a heat bath. The temperature of a molecular system is defined via
the velocity of the particles. Assuming thermodynamic equilibrium is reached each degree of
freedom of a system carries one amount of thermal energy. Considering a particle in an ideal
gas, temperature can be written as
3
1
Etherm = kB T = Ekin = mv 2
2
2
However, for a system with f degrees of freedom temperature is defined as
Etherm =

X1
f
kB T =
mi vi2
2
2
i

20

T =

2 X1
mi vi2
f kB
2
i

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Note that vi is a one dimensional velocity. Using this expression and knowing the degrees of
freedom temperature can be measured numerically during a simulation.
Based on this measurement methods can be applied which correct for the temperature and
drive it towards a desired reference temperature.
3.3.1 Andersen thermostat
The Andersen thermostat follows the idea that the velocities of an idealized gas follow a
Maxwell-Boltzmann distribution. This distribution is given by
s
3
2
m
mv
f (v) =
4v 2 e 2kB T
2kB T
and can be derived from Statistical Mechanics. When simulating a many particle system
controlled by the Andersen thermostat the particles are propagated in time unperturbed
according to Newtons laws. However, collisions occur at uncorrelated Poissonian distributed
times t, where
P (t) = exp(t)
and is the collision rate. Whenever a collision occurs, the velocity of the colliding particle is
randomly drawn from the Maxwell-Boltzmann distribution at the desired reference temperature.
Since collisions occur randomly and uncorrelated and velocities are drawn from the correct
statistical mechanics based distribution the Andersen thermostat produces a correct canonical ensemble. However, as velocities are randomly drawn after every collision the Andersen
thermostat is not suited for investigating dynamic processes such as diffusion.
3.3.2 Berendsen thermostat
The Berendsen thermostat attempts to control temperature by rescaling velocities at every
time step according to

v new = v old

ttime step
1+

1/2
T0
1
T

It is apparent that this method drives the system towards the desired reference temperature
with a damping constant . Nevertheless this method is less thermodynamically profound.
It can be shown that the Berendsen thermostat does not necessarily resemble a canonical
distribution.
Despite this great disadvantage the Berendsen thermostat is widely applied for equilibration purposes as it can relatively fast adjust the temperature. Furthermore, the Berendsen
thermostat perturbs the system only weakly.
3.3.3 Extended Nose-Hoover thermostat
A more sophisticated thermostat based on extended Lagrangians is the Nose-Hoover thermostat. For a simulation of a system with this thermostat the Lagrangian of the system contains

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additional, artificial coordinates which are used for the temperature control. Considering the
usual Lagrangian L(r, v of classical mechanics
L(r, v) = T (v) V (r)
with T (v) being the kinetic energy and V (r) being the potential energy. The momenta
associated with r can be obtained via
p=

L(r, p)
v

To construct isothermal Molecular Dynamics one can introduce an additional coordinate s in

the Lagrangian of the many particle system
LNose (r, v) =

X mi
2

s2 v 2i V (r) +

Q 2 g
s ln s
2

The parameter Q acts as an effective mass for the associated coordinate s. The corresponding
momenta are
LNose
= mi s2 v i
v
LNose
= Qs
ps =
s
pi =

The Hamiltonian of the extended system is then

HNose (r, p) =

X
i

p2s
p2i
ln s
+g
+
U
(r)
+
2
2mi s
2Q

Considering the extended system a micro-canonical ensemble with 6N + 2 degrees of freedom

is generated. The partition function of this ensemble can be written as

1
ZNose =
dps dsdrdp(HNose E)
N!
"
#

2
X p0 2
1
p
g
i
=
dps dsdrdp0 s3N
+ V (r + s + ln s E
N!
2mi
2Q
i

were p0 = p/s was introduced. Defining a new Hamiltonian H(r, p0 ) =

to rewrite the partition function as8



C
3N + 1
0
0
H(p , r)
ZNose =
drdp exp
N!
g

In addition with have to use the following result from distribution theory
[h(s)] = (s s0 )/|h0 (s)|

22

P
i

p0i 2
2mi

+ V (r) allows

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What is going on at the atomic level?

where
exp[E(3N + 1)/g]
C=
g

3N + 1 p2s
dps exp
g
2Q


By setting g = 3N + 1 we see that this partition function corresponds to the canonical

partition function, hence we sample in the canonical ensemble. From the Nose-Hamiltonian
the equations of motion can be derived
pi
HNose
dr i
=
=
dt
pi
mi s2
dpi
U (r)
HNose
=
=
dt
ri
ri
ds
ps
HNose
=
=
dt
ps
Q
P p2i
2mi
dps
HNose
i
=
=
dt
s
s

Using these equations of motion the system can be simulated at a desired reference temperature. Even though this thermostat seems to work fine in theory it can be shown that the
method remains non-ergodic for insufficient chaotic systems such as the harmonic oscillator.

3.4 Pressure control

In order to control the pressure in an Molecular Dynamics simulation we first need a measure
for the pressure of a simulated many particle system. To derive a suitable measure we will
employ the virial theorem


H
qk
= kB T
qk
Each coordinate derivative in this equation is the negative component of a force fi on the ith
particle, so the sum can be rewritten as
*
*
+
+
1 X
1 X

r i r U =
r i f i = N kB T
3
3
i

Here, the force f i represents both the internal forces and the external forces which are related
to the external pressure. The effect of the container walls on the system is given by
*
+
1 X
ext
ri f i
= pV
3
i

In addition, an internal virial can be defined

1X
1X
r i i U =
r i f inter
=W
i
3
3
i

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Then pressure can be related to

pV = N kB T + hW i
Note that in the case of the ideal gas the internal virial vanishes.
3.4.1 Berendsen barostat
The Berendsen barostat is, just like the Berendsen thermostat, a rather simple pressure bath.
An extra term is added to the equations of motion to produce a pressure change. The system
is then designed to obey the equation
p
p p0
=
t
tp
where p0 is the desired pressure and tp some time constant indicating how strong the pressure
is regulated. At each time step the volume of the box is then adjusted by scaling all orthogonal
box vectors by a factor x1/3 , where
r 0 = x1/3 r
x = 1 T

t
(p0 p)
tp

Note that T denotes the isothermal compressibility of the considered medium.

3.4.2 Andersen barostat
The basic idea of the Andersen barostat is to couple the system to an external variable V ,
which denotes the volume of the simulation box. The coupling seeks to mimic the action of a
piston on a real system, where the piston is designed to have mass Q and has the associated
kinetic energy
1
TV = QV 2
2
The potential energy associated with this additional variable arises from the volume energy
contribution
UV = pV
The potential and kinetic energies are then expressed through r and v in terms of scaled
variables
r = V 1/3 s
v = V 1/3 s

The equations of motion can then be readily obtained from the Lagrangian of the system
LV = T + TV U UV

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Note that these methods are designed to simulate a system in the isobaric-isoenthalpic ensemble. Only the additional coupling to a temperature bath provides sampling in the desired
isobaric-isothermal ensemble.
In addition to the presented environment controlling schemes there are also other, more sophisticated methods that carry out the presented basic ideas more carefully and thus provide
better results. Nevertheless the historical starting point for correct thermodynamics in manyparticle simulations were the coupling schemes presented here.

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4 Principles of diffusion
Suppose we have a molecular system of N particles when an intermolecular interaction is
present, such that the ith particle experiment an effective force due to the N 1 particles.
Initially each particle have a coordinate ~ri and velocity ~vi , for i = 1, . . . , N . If we consider
the time evolution of the system we will encounter the system in other configurations respect
to the initial conditions. This is because, the system searches equilibrium states. One of
the processes present in this evolution, between equilibrium states, is the net movement of
particles known as diffusion.
Diffusion refers to the random walk of the center of mass of a tagged particle (the tracer
particle) caused by the collision (hard sphere) with the surrounding particles. The most
important quantity that characterizes the translational diffusion of the center of mass of a
particle is the so-called mean square displacement (MSD) W (t), which is defined as
W (t) =

1
h|~r(t) ~r(0)|2 i
2d

, where ~r(t) is the position vector of the center of mass of the tracer particle at time t, and
hence, ~r(t) = ~r(t) ~r(0) is the particle displacement during a time interval t. A factor 1/2d
has been included into the definition of the MSD for convenience, where d denotes the system
dimension. The reference time t = 0 is taken at the initial experimental time, the brackets
h i denote, in general, an ensemble average.
Suppose that al time t = 0 a particle tracer has a velocity ~v0 , for very short times, when the
molecule velocity has hardly changed under the impact of surroundings, ~r(t) ~r(0) ~v0 t and
hence,
W (t) t2
For long times, when the particle has experienced many collisions with the surroundings, the
MSD changes into a linear function of time, i.e.,
W (t) = Dt
where D is referred as to the single particle diffusion coefficient. We want measure this
quantity to characterize the freedom of movement of the molecules in the system.

26

The life
of molecules

What is going on at the atomic level?

January 14, 2015

Page 27

5 Bash commands
Below is a list of commands that might become useful during the course.
cd directory
cp file
grep expression file
htop
ls
mkdir directory
more file
mv file
rm file/directory
scp file
ssh user@IP
top
vi file
vim file

change directory
copy file
find expression in file
show running processes (more detailed)
list all files and directories that are located in the current directory
create directory
show first lines of file
rename file
delete file (use carefully as files cannot be recovered)
copy file from other computer
connect to user at IP
show running processes
show file
show file
Table 1: List of Bash commands

Below is a list of gromacs executables that might become useful during the course
editconf
genbox
grompp
mdrun
pdb2gmx
trjconv

define box geometries

add water to the .gro
create gromacs readable file .tpr
run simulation from .tpr
create .gro and .top from .pdb
change trajectories

Table 2: List of gromacs executables

27