AMOEBA binding free energies for the SAMPL7 TrimerTrip host–guest challenge.

As part of the SAMPL7 host–guest binding challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for 16 charged organic ammonium guests to the TrimerTrip host, a recently reported acyclic cucurbituril-derived clip host structure with triptycene moieties at its termini. Here we report binding free energy calculations for this system using the AMOEBA polarizable atomic multipole force field and double annihilation free energy methodology. Conformational analysis of the host suggests three families of conformations that do not interconvert in solution on a time scale available to nanosecond molecular dynamics (MD) simulations. Two of these host conformers, referred to as the "indent" and "overlap" structures, are capable of binding guest molecules. As a result, the free energies of all 16 guests binding to both conformations were computed separately, and combined to produce values for comparison with experiment. Initial ranked results submitted as part of the SAMPL7 exercise had a mean unsigned error (MUE) from experimental binding data of 2.14 kcal/mol. Subsequently, a rigorous umbrella sampling reference calculation was used to better determine the free energy difference between unligated "indent" and "overlap" host conformations. Revised binding values for the 16 guests pegged to this umbrella sampling reference reduced the MUE to 1.41 kcal/mol, with a correlation coefficient (Pearson R) between calculated and experimental binding values of 0.832 and a rank correlation (Kendall τ) of 0.65. Overall, the AMOEBA results demonstrate no significant systematic error, suggesting the force field provides an accurate energetic description of the TrimerTrip host, and an appropriate balance of solvation and desolvation effects associated with guest binding. [ABSTRACT FROM AUTHOR]