Alchemical Free Energy Perturbation (FEP) Basics — Hands-on

Learn the principles and practice of alchemical free energy perturbation (FEP) for computing relative binding free energies in drug discovery and mechanistic studies. This module covers thermodynamic cycles, lambda schedules, system setup, simulation execution, convergence checks and realistic interpretation of FEP results for decision support.

Alchemical Free Energy Perturbation (FEP) Basics

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Session Index

Session 1 — FEP Theory & Thermodynamic Cycles Session 2 — System Setup, Topologies & Lambda Schedules Session 3 — Running FEP Simulations & Convergence Checks Session 4 — Result Analysis, Uncertainty & Project Use

Session 1

Fee: Rs 8800

FEP Theory & Thermodynamic Cycles

Free energy, ensembles and alchemical transformations

ΔG definitions and conventions partition functions and ensembles state A to state B transformations

Thermodynamic cycles for binding free energies

relative vs absolute binding ligand mutation cycles protein mutation cycles overview

FEP estimators and statistical background

exponential averaging (Zwanzig) BAR and MBAR ideas sources of bias and variance

Session 2

Fee: Rs 11800

System Setup, Topologies & Lambda Schedules

Preparing protein–ligand systems for FEP

force field and water model choices parameterising ligands consistently box, ions and neutralisation

Dual topology vs single topology approaches

mapping between initial and final states handling ring and scaffold changes soft core potentials overview

Designing lambda schedules and windows

number of lambda points and spacing separate electrostatic and vdW legs planning compute and wall clock time

Session 3

Fee: Rs 14800

Running FEP Simulations & Convergence Checks

Equilibration and production at each lambda

relaxing perturbed systems time step and constraint choices saving data for analysis

BAR/MBAR analysis and ΔG assembly

forward and reverse work distributions overlap between neighbouring lambdas cycle closure checks for networks

Convergence diagnostics and troubleshooting

time series of ΔG estimates identifying problematic windows strategies to improve sampling

Session 4

Fee: Rs 18800

Result Analysis, Uncertainty & Project Use

Interpreting FEP results for ligand series

Theory + Practical

Uncertainty estimates, error bars and comparison to assays

propagating statistical uncertainty correlation with experimental ΔG identifying outliers and systematic shifts

Best practices, communication and integration with design

using FEP with docking and QSAR figures and tables for project reviews documenting methods and limitations

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Alchemical Free Energy Perturbation (FEP) Basics Training | Relative Binding Free Energies

Alchemical Free Energy Perturbation (FEP) Basics — Hands-on