Absolute Free Energy of Binding of Avidin/Biotin, Revisited

I. J. GENERAL; R. DRAGOMIROVA; H. MEIROVITCH

JOURNAL OF PHYSICAL CHEMISTRY B - (Print)

AMER CHEMICAL SOC

Lugar: Washington; Año: 2012 p. 6628 - 6636

1520-6106

The binding of biotin to avidin is one of the strongest in nature with absolute free energy of binding, ΔA0 = −20.4 kcal/mol. Therefore, this complex became a target for a large number of computational studies, which all, however, are based on approximate techniques or simplified models and have led to a wide range of results Therefore, ΔA0 is calculated here by rigorous statistical mechanical methods and models that consider long-range electrostatics. (1) We apply our method, “hypothetical scanning molecular dynamics with thermodynamic integration” (HSMD-TI) to avidin−biotin modeled by periodic boundary conditions with particle mesh ewald (PME). (2) We apply the double decoupling method (DDM) to this system modeled by the spherical solventboundary potential (SSBP) and the generalized solvent boundary potential (GSBP). The corresponding results for neutral biotin, ΔA0 = −29.1 ± 0.8 and −25.2 ± 0.5 kcal/mol aresignificantly lower than the experimental value; we also provide the result for a charged biotin, ΔA0 = −33.3 ± 0.8 kcal/mol. It is plausible to suggest that this disagreement with biotin, ΔA= −33.3 ± 0.8 kcal/mol. It is plausible to suggest that this disagreement with the experiment may stem from ignoring the (positive) contribution of a mobile loop that changes its structure upon ligand binding.