Evaluating Free Energies of

Binding using Amber:

The MM-PBSA Approach

Evaluating Free Energies of
Binding: MM-PBSA
The acronym MM-PBSA stands for Molecular
Mechanics- Poisson Bolzmann Surface Area

The MM-PBSA approach represents the
postprocessing method to evaluate free
energies of binding or to calculate absolute
free energies of molecules in solution.

P.A. Kollman at al., Calculating Structures and Free Energies of Complex
Molecules: Combining Molecular Mechanics and Continuum Models, Acc.
Chem. Res. 2000, 33, 889-897

Evaluating Free Energies of
Binding
G
Bind
= G
AB
G
A
- G
B
G
Bind
A
B
AB
Solvent Solvent
Evaluating Free Energies of
Binding
G
Bind
= G
AB
G
A
- G
B
Approximate G
Bind
as
G
Bind
G
AB
G
A
G
B
Where G
X
is the calculated average free energy

G
X
= E
MM
+ G
Solv
TS
MM
Evaluating Free Energies of
Binding
G
X
= E
MM
+ G
Solv
TS
MM
Where E
MM
is the average molecular mechanical energy:
E
MM
= E
bond
+ E
angle
+ E
tors
+ E
vdw
+ E
elec

G
Solv

is the calculated solvation free energy
TS
MM
is the solute entropy, which can be estimated by using
normal-mode analysis

Evaluating Free Energies of
Binding
G
X
= E
MM
+ G
Solv
TS
MM

Could be easily calculated
I n practice entropy contributions is
usually neglected
Could be computationally expensive
Tend to have a large margin of error
that introduces significant uncertainty
in the result.
?
Evaluating Free Energies of
Binding: Calculating G
Solv
Molecular solvent model
gives gives correct
representation of long-range
electrostatic effects and
correct geometry but could
be hardly used to estimate
solvation energy
Evaluating Free Energies of
Binding: Calculating G
Solv
Continuum model gives fast
estimate of the solvation
energy but could be hardly
used in Molecular Dynamics
simulations
Evaluating Free Energies of
Binding

Compromise:
MD trajectory
One carries out a MD
simulation in a periodic
box with solvent
Snapshots of representative
structures
Evaluate E
MM
, G
Solv
and TS
MM

for every saved snapshot

Evaluating Free Energies of
Binding: Two Approaches
G
Bind
A
B
AB
Solvent Solvent
1. In general case, one carries out three independent MD
simulations: for ligand, receptor, and complex

2. Single trajectory approach: one makes the approximation that
no significant conformational changes occur upon binding so
that the snapshots for all three species can be obtained from a
single trajectory for a complex