(540b) Molecular Dynamics Studies On the Forced Dissociation of Cucurbituril-Guest and Protein-Ligand Systems: Stress, Rupture Force and Binding Affinity

As a major part of this work we perform novel stress, rupture force and binding free energy analyses on forced dissociation molecular dynamics simulations of various cucurbituril-guest systems that emulate single-molecule atomic force microscopy (AFM) experiments, using both stiff and soft spring constants.

Cucurbiturils are ring-shaped molecules (also known as CB[n], where n is the number of glycouril monomers comprising the ring) that have been successfully used as molecular recognition hosts, being able to bind cationic guests with high affinities. Moreover, given their interesting binding properties and fairly easy synthesis, CB[n]s have numerous other applications which include their use as drug carriers, catalysts for supramolecular chemistry, and as basic units for the formation of polyrotaxanes. Given their small size and diverse intra and inter molecular interactions, CB[n]-guest complexes are also optimal test beds for innovative in-silico approaches pertaining to the modeling of biophysical processes.

Particularly, in this study we expand our novel work on the calculation of atomic stresses (Gilson, J. Chem. Theory Comput. 2010, 6, 637–646), measures that provide valuable information about the transition mechanism, primarily due to their ability to isolate the relevant contributions of each interaction type (e.g., bonded, Lennard-Jones, electrostatic interactions) to the structural changes taking place along a particular transition pathway. Remarkably, our stress analyses readily identify the key interactions controlling the forced dissociation of all CB[n]-guest systems studied.

The pulling force profiles derived from our soft-spring-constant simulations were also evaluated in light of Atomic Force Microscopy measurements available for selected CB[n]-guest complexes. Of importance, the peaks of the simulated profiles are in good agreement with the rupture forces obtained in experiments. In contrast, the binding free energies computed from our stiff-spring-constant simulations deviate from those obtained via titration experiments. Nevertheless, our calculations still provide qualitatively consistent information about the relative binding energies of CB[n]-guest systems with distinct affinities.

Lastly, we report our recent efforts on the efficient and accurate identification of stresses, binding free energies and mechanisms of protein-ligand complexes, via optimized forced dissociation calculations.