Accelerated Enveloping Distribution Sampling to Probe the Presence of Water Molecules

Abstract

Determining the presence of water molecules at protein–ligand interfaces is still a challenging task in free-energy calculations. The inappropriate placement of water molecules results in the stabilization of wrong conformational orientations of the ligand. With classical alchemical perturbation methods, such as thermodynamic integration (TI), it is essential to know the amount of water molecules in the active site of the respective ligands. However, the resolution of the crystal structure and the correct assignment of the electron density do not always lead to a clear placement of water molecules. In this work, we apply the one-step perturbation method named accelerated enveloping distribution sampling (AEDS) to determine the presence of water molecules in the active site by probing them in a fast and straightforward way. Based on these results, we combined the AEDS method with standard TI to calculate accurate binding free energies in the presence of buried water molecules. The main idea is to perturb the water molecules with AEDS such that they are allowed to alternate between regular water molecules and non-interacting dummy particles while treating the ligand with TI over an alchemical pathway. We demonstrate the use of AEDS to probe the presence of water molecules for six different test systems. For one of these, previous calculations showed difficulties to reproduce the experimental binding free energies, and here, we use the combined TI–AEDS approach to tackle these issues.

Current State of Open Source Force Fields in Protein–Ligand Binding Affinity Predictions

“…Performing multiple-independent simulation repeats allows for more reliable phase space exploration and uncertainty estimation. , Sampling improvements in relative free energy calculations may also arise by optimally planning the perturbations to be calculated, − altering the alchemical pathway, − using different atom mapping as in the separated topology approach, or using no atom mapping at all as in enveloping distribution sampling. − To sample the water position sufficiently, enhanced water sampling protocols , can be employed. Multiple options exist, such as explicit water perturbations, Monte Carlo moves, ,, or grand canonical ensemble simulations. − …”

“… 34 − 37 To sample the water position sufficiently, enhanced water sampling protocols 38 , 39 can be employed. Multiple options exist, such as explicit water perturbations, 40 Monte Carlo moves, 23 , 41 , 42 or grand canonical ensemble simulations. 43 − 45 …”