Ligand (biochemistry)

Receptor

Mathematics

Principle of maximum entropy

Protein ligand

Statistics

Nursing

Computational chemistry

Estimator

Artificial intelligence

Chemistry

Computer science

Molecular dynamics

Binding affinities

Docking (animal)

Biochemistry

Medicine

Nature Protocols

Designing a reliable computational methodology to calculate protein:ligand standard binding free energies is extremely challenging. The large change in configurational enthalpy and entropy that accompanies the association of ligand and protein is notoriously difficult to capture in naive brute-force simulations. Addressing this issue, the present protocol rests upon a rigorous statistical mechanical framework for the determination of protein:ligand binding affinities together with the comprehensive Binding Free-Energy Estimator 2 (BFEE2) application software. With the knowledge of the bound state, available from experiments or docking, application of the BFEE2 protocol with a reliable force field supplies in a matter of days standard binding free energies within chemical accuracy, for a broad range of protein:ligand complexes. Limiting undesirable human intervention, BFEE2 assists the end user in preparing all the necessary input files and performing the post-treatment of the simulations towards the final estimate of the binding affinity. This protocol describes how to use the Binding Free-Energy Estimator 2 (BFEE2) software to calculate the standard binding free energy of a variety of protein:ligand complexes with different properties.

Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations