SAMPL7 TrimerTrip host-guest binding poses and binding affinities from spherical-coordinates-biased simulations

ZX Sun, JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 35, 105-115 (2021).

DOI: 10.1007/s10822-020-00335-9

Host-guest binding remains a major challenge in modern computational modelling. The newest 7th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge contains a new series of host- guest systems. The TrimerTrip host binds to 16 structurally diverse guests. Previously, we have successfully employed the spherical coordinates as the collective variables coupled with the enhanced sampling technique metadynamics to enhance the sampling of the binding/unbinding event, search for possible binding poses and calculate the binding affinities in all three host-guest binding cases of the 6th SAMPL challenge. In this work, we report a retrospective study on the TrimerTrip host-guest systems by employing the same protocol to investigate the TrimerTrip host in the SAMPL7 challenge. As no binding pose is provided by the SAMPL7 host, our simulations initiate from randomly selected configurations and are proceeded long enough to obtain converged free energy estimates and search for possible binding poses. The calculated binding affinities are in good agreement with the experimental reference, and the obtained binding poses serve as a nice starting point for end-point or alchemical free energy calculations. Note that as the work is performed after the close of the SAMPL7 challenge, we do not participate in the challenge and the results are not formally submitted to the SAMPL7 challenge.

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