FEP+ Methodology

FEP+ is a tool for accurate calculation of the relative binding free energies among congeneric ligands. The key components of FEP+, with their primary citations, are:

• State of the art protein and small molecule force fields, OPLS4 [1]
• Enhanced sampling method, FEP/REST [3,4,5]
• Automated setup and analysis tools [6]
• Robust error estimates through cycle closure [7]
• Perturbations between ligands with different total charges and pKa/tautomeric state correction [8, 9]
• Large scale validation [6]
• GPU hardware acceleration

A brief introduction to FEP theory, the FEP/REST enhanced sampling method, and the cycle closure error estimate are given in the topics listed below.