Molecular
Mechanics
Force
Fields


Basic
Premise



If
we
want
to
study
a
protein,
piece
of
DNA,

biological
membranes,
polysaccharide,
crystal

la;ce,
nanomaterials,
diffusion
in
liquids,…
the

number
of
electrons
(i.e.
the
number
of
energy

calculaAons)
make
quantum
mechanical

calcula-ons
impossible
even
with
present‐day

computers.




Instead,
we
replace
the
nuclei
and
electrons,

and
their
interacAons,
by
new
potenAal

funcAons:
”Classical”
atoms.



Based
on
simple
physical
concepts



Enables
the
systems
under
study
to


be
VERY
large
(100,000
atoms).


 Molecular
mechanics
force
fields


The
molecular
interacAons,
also
known
as
the
potenAals,
together
form
a
force
field,



A
force
field
is
a
mathema8cal
descrip8on
of
the
classical
forces
or
energies

between
par8cles
(atoms).

Energy
=
func%on
of
atomic
posi%ons
(x,y,z)




The
force
field
equa%on
consists
of
several
func%ons
that
describe
molecular

proper%es
both
within
and
between
molecules



The
force
field
also
contains
parameters
(numbers)
in
the
potenAal
funcAons
that
are

tuned
to
each
type
of
molecule
(protein,
nucleic
acid,
carbohydrates)



There
are
many
different
force
field
equaAons
and
parameter
sets



A
force
field
must
be
simple
enough
that
it
can
be
evaluated
quickly,
but
sufficiently

detailed
that
it
reproduces
the
key
features
of
the
physical
system
being
modelled.

 Force
field
classifica8on

In
general,
force
fields
can
be
classified
as
either:



Specific
(many
parameters,
limited
applicability,
high
accuracy)


O>en
developed
in
academic
labs
for
study
of
specific
molecular
classes


or

Generic
(fewer
parameters,
more
generaliza-ons,
wide
applicability,
poor
accuracy)

Easiest
to
use
in
point‐and
click
so>ware



Force
Field
Parameters
can
come
from:



Experimental

sources
(mainly
from
x‐ray
diffrac-on)


or


Theore-cal
calcula-ons
(mainly
from
QM)



Many
force
fields
employ
similar
mathemaAcal
equaAons
but
differ
in
the

parameters
used
in
the
equaAons.

It
is
therefore
extremely
dangerous
mix
to

parameters
between
force
fields.


 Different
Force
Fields:

AMBER
(
Assisted
Model
Building
with
Energy
Refinement).



CHARMM
(Chemistry
at
HARvard
using
Molecular
Mechanics).



GROMOS
(GROenigen
Molecular
SimulaAon)



OPLS
(OpAmized
Parameters
for
Large‐scale
SimulaAons)


MMFF
(the
Merck
Molecular
Force
Field)



DREIDING
Generic
force
field
due
to
Mayo
et
al.
(1990)



UNIVERSAL
(UFF)Generic
force
field
due
to
Rappeet
al.
(1992)



CVFF/PCFF
Force
fields
for
fluorinated
hydrocarbons



MM2,
MM3,
MM4
Developed
by
Allinger
et
al.
for
calculaAons
on
small
molecules



COMPASS
Commercial
force
field
marketed
by
Accelrys
Inc.

 Different
Force
Fields:

AMBER
(
Assisted
Model
Building
with
Energy
Refinement).



CHARMM
(Chemistry
at
HARvard
using
Molecular
Mechanics).



GROMOS
(GROenigen
Molecular
SimulaAon)



OPLS
(OpAmized
Parameters
for
Large‐scale
SimulaAons)


MMFF
(the
Merck
Molecular
Force
Field)



DREIDING
Generic
force
field
due
to
Mayo
et
al.
(1990)



UNIVERSAL
(UFF)Generic
force
field
due
to
Rappeet
al.
(1992)



CVFF/PCFF
Force
fields
for
fluorinated
hydrocarbons



MM2,
MM3,
MM4
Developed
by
Allinger
et
al.
for
calculaAons
on
small
molecules



COMPASS
Commercial
force
field
marketed
by
Accelrys
Inc.

 Force
Field
Poten8al
Func8ons


The
potenAal
funcAons
may
be
divided
into
bonded
terms,
which
give
the
energy

contained
in
the
internal
degrees
of
freedom,
and
non‐bonded
terms,
which

describe
interac8ons
between
molecules.


E pot = ∑V + ∑Vθ + ∑Vτ + ∑V

r vanderWaals + ∑Velectrostatics
bonds angles torsions atoms atoms

Poten8als
between
bonded
atoms
 Poten8als
between
non‐bonded
atoms


Total
poten8al
Energy,
Epot
or
Vtot

 Force
Field
Poten8al
Energy
Func8ons

 σ 12  σ 6 
ij ij
VvanderWaals = 4ε   −    (John
Lennard‐Jones
–
1931)


Rij
  Rij   Rij  
 
i
 j

qi q j
VElectrostatic = (Charles
Augus-n
de
Coulomb
‐1785)


4πεRij

rij
 1 ij 2
i
 j
 Vbonds
2
(
= k r rij − rij0 )
(Robert
Hooke
‐
1660)

 k
 j

τijkl

j
 i
 1 2
(
Vangles = kθijk θ ij − θ ij0
2
)
l
 i

θijk

k 1 ijkl
Vtorsions = ∑ k
n n
(1 − cos(nτ ))
2
(Jean
Bap-ste
Joseph
Fourier
–
1822)


 AlternaAvely,
a
power‐series
expansion
of
the
Morse
potenAal
can
be
used



Graphical
comparison
of
Morse
and
power
law
potenAals


Problem
with
harmonic
approximaAon:



Bonds
cannot
break
(essence
of
Molecular
Mechanics;
no
bonds
are
broken
or
formed,

cannot
be
used
for
chemical
reacAons).

 Torsion
Angle
or
Dihedral
Angle
Energy


The
torsional
energy
is
defined
between
every
four
bonded
atoms
(1‐4
interacAons),

and
depends
on
the
torsion
(aka
dihedral)
angle
ϕ
made
by
the
two
planes

incorporaAng
the
first
and
last
three
atoms
involved
in
the
torsion


Torsion
terms
account
for
any
interacAons
between
1‐4
atom
pairs
that
are
not
already

accounted
for
by
non‐bonded
interacAons
between
these
atoms



For
example:
they
could
be
used
to
describe
barriers
to
bond
rotaAon
from
electron

delocalizaAon
(double
bonds
or
parAal
double
bonds),
or
stereo‐electronic
effects

 Torsion
Example
–
The
Single
Bond



Using
the
standard
cos3φ
potenAal,
there
are
three
equilibrium
posiAons:
ϕ
=
180°

(trans
state)
and
±
60°
(gauche
states).



In
pracAce,
the
energies
of
the
gauche
states
are
slightly
different
than
that
of
the

trans
state,
depending
on
the
atoms
involved
in
the
torsion.

To
introduce
a
difference
between
the
stabiliAes
of
the

gauche
and
trans
conformaAons,
the
torsion
funcAon
can
be

expanded
with
addiAonal
terms,
each
with
it’s
unique

contribuAon
to
the
rotaAonal
energy:

 Electrosta8cs

Difference
in
electronegaAvity
between
atoms
generates
unequal
charge

distribuAon
in
a
molecule



Omen
electronegaAvity
differences
are
represented
as
fracAonal
point
charges
(q)

within
the
molecule
(normally
centered
at
the
nuclei
(parAal
atomic
charges)



ElectrostaAc
interacAon
energy
is
calculated
as
a
sum
of
interacAons
between

parAal
atomic
charges,
using
Coulombs
law



Naturally,
this
equaAon
is
also
used
for
modeling
interacAons
between
integral

charges,
such
as
between
ions


qi q j
VElectrostatic =
4πεRij
The
problem
with
this
approach
is
that
there
is
no
such
thing
as
a
fracAonal
electron,

therefore
there
is
no
perfect
method
to
derive
the
parAal
atomic
charges

 Van
der
Waals
Interac8ons


Non‐bonded
interacAon
that
are
not
electrostaAc
(e.g.
between
atoms
in
noble

gas)
are
labeled
van
der
Waals
interacAons



Contains
dispersion
and
short‐range
components



Dispersion
interacAons
always
aoracAve.

Arise
from
instantaneous
dipoles
that

occur
during
fluctuaAons
within
the
molecular
electron
cloud




Short‐range
interacAons
are
always
unfavorable.
Also
labeled
exchange,
or

overlap,
forces.

They
occur
between
electrons
with
the
same
spin
so
they
do
not

occupy
same
region
in
space
(Pauli
exclusion
principle)

 SUMMARY
–
Force
Field
Terms

ElectrostaAc
energy
is
represented
using
a
set
of
parAal
atomic
charges



van
der
Waals
energy
has
both
weakly
aoracAve
and
strongly
repulsive
components
and

arises
from
represents
electron
correlaAon



The
dispersion
term
is
always
negaAve
whereas
short‐range
energy
is
always
repulsive.




Torsion
terms
describe
bond
rotaAonal
properAes
that
arise
from
non‐classical
effects,

such
as
electron
delocalizaAon



The
remaining
bond
and
angle
terms
describe
covalent
bonding


Once
we
have
our
force
field,
what
can
we
do
with
it?



–Energy
minimisaAon

–
Molecular
Dynamics

–ConformaAonal
analysis



The
accuracy
of
the
output
from
all
these
techniques
will
obviously
be
sensi8ve
to
a

greater
or
lesser
extent
on
the
parameteriza8on
of
the
force
field