Combining Alchemical Transformation with a Physical
Pathway to Accelerate Absolute Binding Free Energy Calculations of
Charged Ligands to Enclosed Binding Sites
posted on 2020-03-09, 19:39authored byJeffrey Cruz, Lauren Wickstrom, Danzhou Yang, Emilio Gallicchio, Nanjie Deng
We present a new
approach to more accurately and efficiently compute
the absolute binding free energy for receptor–ligand complexes.
Currently, the double decoupling method (DDM) and the potential of
mean force method (PMF) are widely used to compute the absolute binding
free energy of biomolecular complexes. DDM relies on alchemically
decoupling the ligand from its environments, which can be computationally
challenging for large ligands and charged ligands because of the large
magnitude of the decoupling free energies involved. In contrast, the
PMF method uses a physical pathway to directly transfer the ligand
from solution to the receptor binding pocket and thus avoids some
of the aforementioned problems in DDM. However, the PMF method has
its own drawbacks: because of its reliance on a ligand binding/unbinding
pathway that is free of steric obstructions from the receptor atoms,
the method has difficulty treating ligands with buried atoms. To overcome
the limitation in the standard PMF approach and enable buried ligands
to be treated, here we develop a new method called AlchemPMF in which
steric obstructions along the physical pathway for binding are alchemically
removed. We have tested the new approach on two important drug targets
involving charged ligands. One is HIV-1 integrase bound to an allosteric
inhibitor; the other is the human telomeric DNA G-quadruplex in complex
with a natural product protoberberine buried in the binding pocket.
For both systems, the new approach leads to more reliable estimates
of absolute binding free energies with smaller error bars and closer
agreements with experiments compared with those obtained from the
existing methods, demonstrating the effectiveness of the new method
in overcoming the hysteresis often encountered in PMF binding free
energy calculations of such systems. The new approach could also be
used to improve the sampling of water equilibration and resolvation
of the binding pocket as the ligand is extracted.