Chemistry Reference
In-Depth Information
aggregation diseases and developing peptide-based therapeutics, is understanding
the molecular determinants of the relative propensities of proteins to aggregate in
a cellular environment. The authors report a crucial role of the surrounding water
in determining the aggregation propensity of proteins both
in vitro
and
in vivo
[370].
SIMULATIONS OF FREE ENERGIES
We commonly characterize the interactions of most ligands with their binding
sites in terms of binding affinities. They describe the strength with which a ligand,
like a drug, binds to a receptor. The energy left once you have paid the tax to
entropy is the free energy, which defines binding affinities. Enthalphy is the
energy of interaction for a single binding pose orientation in the pocket. Enthalpy
involves hydrogen bonds, polar interactions, van der Waals interactions. The sum
over all possible poses in the pocket yields entropy (involves loss of degrees of
freedom, gain of vibrational modes, loss of solvent/protein structure) [583-652].
The binding affinity is defined in terms of the strength between the ligand and protein
interactions. The dissociation constant (Kd) is a measure of whether the interaction
will be formed in solution or not. The binding affinity characterizes the binding of
ligand and receptor molecules in solution. It is described by the molar Gibbs free
energy which is related to
K
d
via
ΔG = RTln (
K
d
) where R is the ideal gas constant and
T is the temperature. The orientation of the ligand in a protein pocket is the binding
pose. The interaction energy for a singly pose is the enthalphy. The sum over all
possible poses is the entropy. Entropy is lower when a single pose is favored. A
system (constant temperature and pressure) will evolve towards equilibrium in the
direction of decreasing Gibbs free energy. For changes (ΔS) in entropy and changes
(ΔH) in enthalpy we have (ΔG=ΔH - TΔS). There is a preference for lower potential
energies. Thermal motion disrupts bond formation. The equilibrium between ligand A
and its receptor B, as a phenomenon of association or dissociation, yields
ΔG = RTln((AB)
eq
/[A]
eq
[B]
eq
). Ligands with high binding affinity require
comparatively lower concentrations to occupy maximum sites.
Accurate values of ΔG are required for determining binding affinities (free energy
simulations). It is necessary to probe the most populated states. Good quality
