The Calculation of Enthalpy and Entropy

Differences???

(Housekeeping Details for the
Calculation of Free Energy Differences)

first edition: p. 493-502
second edition: p. 574-585
The Calculation of Enthalpy and Entropy
Differences
Free energies can now be calculated with errors of less
than 1 kcal/mol in favorable cases.
Enthalpy and entropy differences for solvation could be
calculated by simulating the two systems separately and
taking the differences in the total.

Leads to much larger errors than for the free energy
since the free energy reduces to interaction terms only
involving the solute.

For example: The solvent-solvent interaction term which
contributes the so-called cavity (solvent reorganization)
term to the energy is said to be canceled exactly by a
corresponding term in the entropy.
Yu, H.-A.; Karplus, M. J. Chem. Phys. 1988, 89, 2366-2379.
Partitioning the Free Energy
If the thermodynamic integration method is used the
overall free energy can be partitioned into individual
contributions.







However, while the total free energy is a state function the
individual contributions are not.
( )
}
=
=
c
c
= A
1
0
,

d A
N N
r p H
( )
( )

+ A + A =
+
c
c
+
c
c
= A
} }
=
=
=
=
angles bonds
1
0
angles
1
0
bonds
A A
d d A

H
H
Partitioning the Free Energy
Calculation of the free energy differences by thermodynamic
integration:











When performing this procedure on individual contributions, energy is
transferred between the contributors. For example relieving strain in a
bond angle may increase the potential energy in certain bond
distances.
Partitioning the Free Energy
A common practice is to partition the free energy into
contributions from the van der Waals and electrostatic
interactions.

The biotin/streptavidin complex has
an extremely strong association
constant (-18.3 kcal/mol).

The favorable electrostatic interaction, from H-bonding,
was canceled by the free energy of interaction of biotin
with water.
However there was a very large van der Waals interaction.
N
N
S
H
H
COOH
H
H
H
O
biotin
Partitioning the Free Energy
Strong van der Waals interaction.
Potential Pitfalls with Free Energy Calculations
Two major sources of error: 1) Hamiltonian. 2) insufficient
sampling of phase space.
Inadequate sampling:
errors may be identified by running the simulation for
longer periods of time (molecular dynamics (MD)) or
for more iterations (Monte Carlo (MC)).
The perturbation may be run in the forward and reverse
directions. The difference in the calculated energy
values, hysteresis, gives a lower bounds estimate of the
error.
Note, very short simulations may give almost 0 hysteresis
while the errors may still be large.
Implementation Aspects
Simulation Method:
Molecular dynamics is almost always used for systems
with significant degree of conformational flexibility.
Monte Carlo gives good results for small rigid
molecules.
Thermodynamic perturbation or integration preferred
over the slow growth methods.
Slow growth suffers from Hamiltonian lag and
adding additional values of requires rerunning the
simulation from scratch.

= =
= =
+
= A
1 ;
0 ; 1
1
) (

step
N i
i
i i
A H - H
Implementation Aspects
Coupling Parameter ()
o does not have to be a constant value. Could use
small values when the free energy is changing quickly
and large values when the free energy is changing
slowly. (Dynamically modified windows)

Choice of Pathway
A change that involves high energy barriers will require
much smaller increments in to insure reversibility
than a pathway that proceeds via a lower barrier.
Implementation Aspects
Single-topology:







Dual Topology:
Both molecular topologies are maintained, but do not
interact with each other.
The simplest Hamiltonian that describes the interaction
between these groups and the environment is a linear
relationship:
H
H
H
H
O X
H
H
X
H
O H
C H
3
H
O
C H
2
H
O H

The molecular topology at
all stages is a union of the
initial and final states,
using dummy atoms where
necessary.
( ) ( )
X Y
1 H H H + =
Implementation Aspects
Dual Topology:

Can result in a singularity in the function for which an ensemble
average is to be formed.
Problem with thermodynamic integration where the derivative of the
parameterized Hamiltonian with respect to is the observable.
One solution when performing MC is to change the scaling factors:


When n > 4 the free energy difference is always finite and can be
integrated numerically.
However this results in difficulties in calculating the first and second
derivatives of the potential energy function required for MD.

Solution: Soft Core Potentials.
( ) ( )
X Y
1 H H H
n
+ =
n
Implementation Aspects
Soft Core Potential:
The traditional Lennard-Jones interaction can be replaced:
















Similar expressions can be developed for for electrostatic interactions.

( )
| |
| |
|
|
|
.
|

\
|
+

+
=
6 6
LJ
6
2
6 6
LJ
12
4
ij ij
ij
ij ij
ij
ij
LJ
ij
r
r
v
o o
o
o o
o
c
Atom-atom separation
P
o
t
e
n
t
i
a
l

e
n
e
r
g
y

= 1
= 0
Where o determines the
softness of the interaction,
removing the singularity.
Potentials of Mean Force
May wish to examine the Free Energy as a function of some
inter- or intramolecular coordinate. (ie. Distance, torsion
angle etc.)
The free energy along the chosen coordinate is known as the
Potential of Mean Force (PMF).
Calculated for physically achievable processes so the point of
highest energy corresponds to a TS.
Simplest type of PMF is the free energy change as the
separation (r) between two particles is varied.
PME can be calculated from the radial distribution function
(g(r)) using:


Recall: g(r) is the probability of finding an atom at a distance r from another
atom.

constant ) ( ln ) (
B
+ = r g T k r A
Potentials of Mean Force
Problem: The logarithmic relationship between the PMF and
g(r) means a relatively small change in the free energy (small
multiple of k
B
T may correspond to g(r) changing by an order
of magnitude.
MC and MD methods do not adequately sample regions
where the radical distribution function differs drastically
from the most likely value.

Solution: Umbrella Sampling.
The coordinates of interest are allowed to vary over their
range of values throughout the simulation. (Subject to a
potential modified using a forcing function.)
Umbrella Sampling
The Potential Function can be written as a perturbation:


Where W(r
N
) is a weighting function which often takes a quadratic form:


Result: For configurations far from the equilibrium state, r
0
N
, the
weighting function will be large so the simulation will be biased along
some relevant reaction coordinate.

The Boltzmann averages can be extracted from the non-Boltzmann
distribution using:




Subscript W indicates that the average is based on the probability P
W
(r
N
),
determined from the modified energy function V (r
N
).
) ( ) ( ) (
N N N
W r r r + =
'
V V
2
0
) ( ) (
N N
W
N
k W r r r =
| |
| |
W
N
W
N N
T k W
T k W A
A
B
B
/ ) ( exp
/ ) ( exp ) (
r
r r
+
+
=
Umbrella Sampling
This free energy perturbation method can be used with MD
and MC.
Calculation can be broken into a series of steps characterized
by a coupling parameter with holonomic constraint
methods used to fix the desired coordinates. (ie. SHAKE)