Can Absolute Free Energies of Association Be Estimated from Molecular Mechanical Simulations? The Biotin−Streptavidin System Revisited

Employing state-of-the-art molecular dynamics protocols, we carried out free energy calculations in the ( N, P, T ) ensemble on a fully hydrated biotin−streptavidin assembly of 27 702 atoms. The reported absolute binding free energy of −16.6 ± 1.9 kcal/mol is in good agreement with the experimental estimate of −18.3 kcal/mol by Weber et al. [ J. Am. Chem. Soc. 1992, 114, 3197−3200]. These simulations illustrate that the use of massively parallel architectures in conjunction with efficient algorithms allows us to tackle biologically relevant problems involving large molecular systems and to access key properties, like the association of a protein with its ligand, under rigorous thermodynamic conditions.