Transcript MM-PBSA in Amber9

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
ΔGBind
A
AB
B
Solvent
Solvent
ΔGBind = ΔGAB
– ΔG A - ΔG B
Evaluating Free Energies of
Binding
ΔGBind = ΔGAB
– ΔG A - ΔG B
Approximate ΔGBind as
ΔGBind ≈
Where
GAB – GA – GB
GX is the calculated average free energy
ΔG X =
EMM + GSolv – TSMM
Evaluating Free Energies of
Binding
ΔG X =
Where
EMM + GSolv – TSMM
EMM is the average molecular mechanical energy:
EMM = Ebond + Eangle + Etors + Evdw + Eelec
GSolv is the calculated solvation free energy
– TSMM is the solute entropy, which can be estimated by using
normal-mode analysis
Evaluating Free Energies of
Binding
ΔG X =
EMM + GSolv – TSMM
Could be easily calculated
• In 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 GSolv
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 GSolv
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 EMM , GSolv and –TSMM
for every saved snapshot
Evaluating Free Energies of
Binding: Two Approaches
ΔGBind
A
Solvent
AB
B
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