Assessing the Predictive Power of Relative Binding Free Energy Calculations for Test Cases Involving Displacement of Binding Site Water Molecules

Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?

Our interest is relative binding free energy (RBFE) calculations based on molecular simulations. These are promising tools for lead optimization in drug discovery, computing changes in binding free energy due to modifications of a lead compound. However, in the "alchemical" framework for RBFE calculations, some types of mutations have the potential to introduce error into the computed binding f...

Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A

The periplasmic oligopeptide binding protein A (OppA) represents a well-known example of water-mediated protein-ligand interactions. Here, we perform free-energy calculations for three different ligands binding to OppA, using a thermodynamic integration approach. The tripeptide ligands share a high structural similarity (all have the sequence KXK), but their experimentally-determined binding fr...

How To Deal with Multiple Binding Poses in Alchemical Relative Protein–Ligand Binding Free Energy Calculations

Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of the most rigorous methods to calculate relative binding free energies. However, for cases where there are high energy barriers separating the relevant conforma...

Free energy calculations and ligand binding.

Computation of the binding affinities of catechol-O-methyltransferase inhibitors: Multisubstate relative free energy calculations

Alchemical free energy simulations are amongst the most accurate techniques for the computation of the free energy changes associated with noncovalent protein-ligand interactions. A procedure is presented to estimate the relative binding free energies of several ligands to the same protein target where multiple, low-energy configurational substates might coexist, as opposed to one unique struct...