Biology Reference
In-Depth Information
as the sum of a cavity term and a solute-solvent van der Waals term, is
assumed to be proportional to the solvent-accessible surface area (SASA):
D
G
np,solv
=
g
SASA
+
b
.
This well-known and often-used approximation comes from the fact that
the
G
solv
of saturated nonpolar hydrocarbons is linearly related to the
SASA.
46,47
Several linear models exist. The surface tension
∆
and the con-
stant
b
can be set to 0.00542 kcal mol
−1
Å
−2
and 0.92 kcal mol
−1
, respec-
tively, if
γ
∆
G
elec,solv
is calculated from PB models.
48
Values of 0.0072 kcal
mol
−1
Å
−2
and 0 kcal mol
−1
,
49
or 0.005 kcal mol
−1
Å
−2
and 0 kcal mol
−1
,
can be used together with GB models.
50
Recently, an alternative model
for
G
np,solv
using a cavity solvation free energy term plus an explicit
solute-solvent van der Waals interactions energy term has been
tested; this model led to better results in estimating
∆
G
bind
for
the Ras-Raf association, although the transferability of the results was
questioned.
50
The entropy term, due to the loss of degrees of freedom upon asso-
ciation, is decomposed into translational (
S
trans
); rotational, (
S
rot
); and
vibrational (
S
vib
); contributions. These terms are calculated using stan-
dard equations of statistical mechanics.
51
S
rot
is a function of the moments
of inertia of the molecule, whereas
S
trans
is a function of the mass and the
solute concentration.
S
trans
is the only term in the free energy of an ideal
solution that depends on solute concentration, leading to the concentra-
tion dependence of the binding reactions.
S
vib
is calculated with the quan-
tum formula from a normal mode analysis (NMA).
51
A quasi-harmonic
analysis of the MD simulations is also possible; however, it has been
found that it does not always yield convergent values, even using very
long MD simulation trajectories, and also led to large deviations from the
results obtained with NMA, giving an overall unreasonable entropic con-
tribution.
50
In the standard MM-PB (GB)SA protocol, the energy terms are aver-
aged over 200-500 frames extracted from MD simulation trajectories,
typically performed in explicit solvent, using periodic or stochastic
boundary conditions. Explicit water molecules are removed prior to
∆
