Free-energy calculations - Theoretical Biophysics Group

∆ Abinding
A
protein + ligand A
0
∆ Amutation
protein + ligand B
B
∆ Abinding
Free-energy perturbation calculations “Alchemical transformations”
protein ... ligand A
1
∆ Amutation
protein ... ligand B
29 PEARLMAN, CHARIFSON (2001); CHIPOT ET AL. (2005)
In many instances, determining relative binding free energies
for a series of ligands is preferred over a single
binding free energy.
This is the case, for example, potential inhibitors of a target
protein are sought in the context of computer–aided
drug design. 29
This can be handled by repeating the “absolute” transformations
for each ligand of interest.
There is an alternate pathway, likely to be more efficient:
Mutation of ligand A into ligand B in both the bound and
the free states, following a different thermodynamic cycle.
Chris Chipot Free-energy calculations