Living Journal of Computational Molecular Science · 2023 · 12 citations · 0 references
Natural SciencesBiophysicsChemistryComputational BiophysicsComputational ChemistryPhysical ChemistryBinding Affinity PredictionBinding ThermodynamicsComputational Molecular BiophysicsMolecular DynamicsMolecular ModelingMolecular SimulationBinding Free EnergyFree Energy PerturbationFree Energy Perturbation ModelingLigand-binding EnergeticsMolecular Dynamics-based Affinity EstimationProtein-ligand Binding Free EnergyProtein-ligand Binding Free Energy CalculationsProtein-ligand Binding Thermodynamics
Free Energy Perturbation (FEP) is a powerful but challenging computational technique for estimating differences in free energy between two or more states. This document is intended both as a tutorial and as an adaptable protocol for computing free energies of binding using free energy perturbations in NAMD. We present the Streamlined Alchemical Free Energy Perturbation (SAFEP) framework. SAFEP shifts the computational frame of reference from the ligand to the binding site itself. This both simplifies the thermodynamic cycle and makes the approach more broadly applicable to superficial sites and other less common geometries. As a practical example, we give instructions for calculating the absolute binding free energy of phenol to lysozyme. We assume familiarity with standard procedures for setting up, running, and analyzing molecular dynamics simulations using NAMD and VMD. While simulation times will vary, the human tasks should take no more than 3 to 4 hours for a reader without previous training in free energy calculations or ex- perience with the VMD Colvars Dashboard. Sample data are provided for all key calculations both for comparison and readers’ convenience.