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 fre e energy calculations in the (N, P, T) ensemble on a fully hydrated biotin- streptavidin assembly of 27702 atoms. The reported absolute binding free en ergy of -16.6 +/- 1.9 kcal/mol is in good agreement with the experimental e stimate of -18.3 kcal/mol by Weber et al. [J. Am. Chem. Soc. 1992, 114, 319 7-3200]. These simulations illustrate that the use of massively parallel ar chitectures in conjunction with efficient algorithms allows us to tackle bi ologically relevant problems involving large molecular systems and to acces s key properties, like the association of a protein with its ligand, under rigorous thermodynamic conditions.