SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip is synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host are characterized. The challenge provides only structures of the host and the guests, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates show significant deviations. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is already very long and the intermediate spacing is very dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way.