3 research outputs found
New molecular simulation methods for quantitative modelling of protein-ligand interactions
The main theme of this work is the design and development of new molecular
simulation protocols, to achieve more accurate and reliable estimates of
free energy changes for processes relevant to the structure-based drug design.
The works starts with an insight into the reproducibility problem for alchemical
free energy calculations. Even if simulations are run with similar input
files, the use of different simulation engines could give different free energy
results. As part of a collaborative effort, the implementation details of AMBER,
GROMACS, SOMD and CHARMM simulation codes were studied and
free energy protocols for each software were validated to converge towards a
reproducibility limit of about 0.20 kcal.mol-1 for hydration free energies of
small organic molecules.
Following, new simulation methods for the estimation of lipophilicity coefficients (log P and log D) for drug like molecules were developed and validated.
log P values were computed for a dataset of 5 molecules with increasing
fluorination level. Predictions were in line with the experimental measures
and the simulations also allowed new insights into the water-solute interactions
that drive the partitioning process. Then, as part of the SAMPL5
challenge, log D values for 53 drug-like molecules were computed. In this
context two different simulation models were derived in order to take into
account the presence of protonated species. The results were encouraging
but also highlighted limits in alchemical free energy modelling.
As an additional task of the SAMPL5 contest, three different protocols
were validated for predicting absolute binding affinities for 22 host-guest systems.
The first model yielded a free energy of binding based on free energy
changes in solvated and complex phase; the second added the long range
dispersion correction to the previous model; the third one used a standard
state correction term. All three protocols were among the top-ranked submission
in SAMPL5, with a correlation coefficient R2 of about 0.7 against
experimental data.
Finally, the origins and magnitude of the finite size artefacts in alchemical
free energy calculations were investigated. Finite size artefacts are especially
predominant in calculations that involve changes in the net-charge of a solute.
A new correction scheme was devised for the Barker Watts Reaction
Field approach and compared with the literature. Hydration free energy calculations
on simple ionic species were carried out to validate the consistency
of the scheme and the approach was further extended to host-guest binding
affinities predictions
Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods
We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R2) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R2 = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods