Molecular tweezers offer promising efficacy in a number of applications, including, and perhaps most exciting, the inhibition of the toxic aggregation of intrinsically disordered proteins via targeted binding at specified amino acid sites. Molecular Dynamics (MD) simulations provide an incredibly useful tool in exploring chemical processes. For instance, free-energy decompositions can isolate contributions to binding free-energy, such as solvent-mediated interactions. However, reliable MD simulations depend on reliable force-field (FF) parameter sets. As a specialized class of supramolecular hosts, molecular tweezers possess unique chemical properties, such as their conformational flexibility and their functional group induced electrostatic interactions with guest molecules. FF parameter sets used for simulations must reflect this uniqueness. And although generalized force-field Parameter sets are widely used for computational studies of Molecular Tweezers, generalized parameter sets are not specifically intended for highly unique classes of molecules such as Host-Guest complexes and more specifically, molecular tweezers. Our goal is to evaluate the performance and reliability of these generalized FF’s to predict binding free energies under varying solution conditions that reflect experimental results. Here, we develop reliable simulation protocols to investigate binding free-energies which explicitly consider slow degrees of freedom that play a critical role for the interaction of molecular tweezers and cationic amino acids. Our simulations indicate that the rotation of molecular tweezer’s phosphate functional groups, depending on which generalized FF is used, can have correlation times greater than 10 ns indicating that accurate binding free-energy calculations would require a high computational cost. To mitigate these sampling issues, without greatly increasing the computational cost of our simulations, we optimize simulation protocols for 2D Umbrella sampling simulations to combine the free energy surface of phosphate rotations with alchemical binding free energies for each generalized FF parameter set.

Calculating binding free-energies for molecular tweezer host-guest systems

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.