<p>The prediction of host-guest binding
affinities with computational modelling is still a challenging task. In the 7<sup>th</sup>
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. </p>