Energy Driven Undocking of FKBP12 Ligands Using
Hamiltonian Replica Exchange Simulations
Francesca Nerattini and Piero Procacci
Dipartimento di Chimica, Università di Firenze
January 29, 2014
Methods
The Absolute binding free energy for drug-receptor complexes are determined using Hamiltonian Replica Exchange
(H-REM). In the extended multicanonical system, bound and unbound states are sampled using a H-REM scaling
protocol whereby the drug-receptor interactions are progressively weakened with increasing replica index. A weak
tethering potential prevents the drug to drift away in the bulk solvent. The absolute free energy of binding is
computed as
∆G = −kB T ln(pb /pu ) − kb T ln(Veff /V0)
where V0 and Veff are the standard volume and the mean accessible volume of the ligand imposed by tethering
potential. The probability for the bound and unbound state, pb , pu are evaluated using the full Generalized Ensemble
statistic exploiting the Multiple Bennett
acceptance
Ratio
re-weighting
technique,
i.e.

 

N
X
pb 
=
pu
N
X
wi (xi )H(F xi )) / 
i
wi (xi )[1 − H(F (xi ))]
i
with H being an Heaviside step function discriminating bound and unbound states based on appropriately defined
contact function F and w are the MBAR weights.
The algorithm
Schematic representation of HREM simulation of a tight binding ligand
(in red) with solute-solvent counter-scaling. Each horizontal line
represents a replica simulation in the generalized ensemble with scaled
active-site-drug potential function. The thickness of the line for each
replica is proportional to the MBAR weight of the corresponding GE
configurations. Unbound states are found only in the last replicas with
a small MBAR weight.
The system(s)
Six FKBP12 complexes have been simulated: SB3-FKBP12(wt) and -FKBP12(Ile56Asp);
N-Elte-FKBP12(wt) and -FKBP12(Ile56Asp); FK506-Elte-FKBP12(wt) and -FKBP12(Ile56Asp);
Results
Figure: Extrapolation of the binding free energy as a function of the number of contacts of the FK506
natural drug (left) and of the new synthetic N-Elte compound (right) vs native FKBP12 and the
mutant I56D-FKBP12
Simulation Details
H-REM Molecular Dynamics simulation of solvated FKBP12 with the
ligands sb3, N-Elte and the Tacrolimous natural drug lasting from 4 to
10 ns launched on 16 replicas. All atom Amber03 force field, 15000
atoms in total, multiple time step simulation (0.5 to 12. fs steps) with
Particle Mesh Ewald for electrostatics.
Figure: Residues contribution to the binding for FK506 (left) and N-Elte (right)