posted on 2013-12-23, 00:00authored byE. Prabhu Raman, Wenbo Yu, Sirish K. Lakkaraju, Alexander D. MacKerell
The
site identification by ligand competitive saturation (SILCS)
method identifies the location and approximate affinities of small
molecular fragments on a target macromolecular surface by performing
molecular dynamics (MD) simulations of the target in an aqueous solution
of small molecules representative of different chemical functional
groups. In this study, we introduce a set of small molecules to map
potential interactions made by neutral hydrogen bond donors and acceptors
and charged donor and acceptor fragments in addition to nonpolar fragments.
The affinity pattern is obtained in the form of discretized probability
or, equivalently, free energy maps, called FragMaps, which can be
visualized with the target surface. We performed SILCS simulations
for four proteins for which structural and thermodynamic data is available
for multiple diverse ligands. Good overlap is shown between high affinity
regions identified by the FragMaps and the crystallographic positions
of ligand functional groups with similar chemical functionality, thus
demonstrating the validity of the qualitative information obtained
from the simulations. To test the ability of FragMaps in providing
quantitative predictions, we calculate the previously introduced ligand
grid free energy (LGFE) metric and observe its correspondence with
experimentally measured binding affinity. LGFE is computed for different
conformational ensembles and improvement in prediction is shown with
increasing ligand conformational sampling. Ensemble generation includes
a Monte Carlo sampling approach that uses the GFE FragMaps directly
as the energy function. The results show that some but not all experimental
trends are predicted and warrant improvements in the scoring methodology.
In addition, the potential utility of atom-based free energy contributions
to the LGFE scores and the use of multiple ligands in SILCS to identify
displaceable water molecules during ligand design are discussed.