Brownian dynamics simulations of binding mRNA cap analogues to eIF4E protein

The binding of five analogues of the 5'-end mRNA cap, differing in their electrostatic and hydrodynamic properties, to the eukaryotic initiation factor eIF4E was simulated by means of Brownian dynamics methods. Electrostatic and hydrodynamic models of eIF4E protein and the ligands were prepared using established molecular electrostatics and hydrodynamics simulation methods for predicting ionization states of titratable groups, adequate for given experimental conditions, and for computing their translational and rotational diffusion tensors, respectively. The diffusional encounter rate constants obtained from simulations are compared with bimolecular association rate constants resulting from stopped-flow spectrofluorimeter measurements. A very good agreement between simulations and experiments was achieved, which indicates that the kinetics of binding 5'-mRNA caps can be satisfactory explained by referring to the Brownian motion of the particles with the electrostatic steering of the ligands toward the eIF4E binding site and electrostatic desolvation contributions upon complex formation.