Direct Measurement of the Kinetics and Thermodynamics of Association of Hydrophobic Molecules from Molecular Dynamics Simulations

A detailed study of the kinetics and thermodynamics of associations of model hydrophobic molecules is likely to be valuable for understanding the fundamental driving forces for processes such as protein folding and protein-protein association. To this end, we present results from a series of 500 ns long molecular dynamics (MD) simulations examining associations of 13 types of different alkane pairs in explicit water. In addition to providing accurate measurements of the association thermodynamics, the unbiased nature of the configurational sampling in the MD simulations allows the association and dissociation kinetics to be directly quantified. We show that by choosing a suitable reaction coordinate, the computed free energies of all of the alkane-alkane complexes can be linearly related to their buried molecular surface areas, that their dissociation kinetics can be reliably estimated from the height of the barrier on the computed free energy surfaces, and that their association kinetics are effectively diffusion-limited.