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SAMPL7 TrimerTrip host–guest binding affinities from extensive alchemical and end-point free energy calculations

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Abstract

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 was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, 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 retrospectively. 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 perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. 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 long and the intermediate spacing is 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. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent.

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Acknowledgements

This work is supported by China Postdoctoral Science Foundation. Dr. Zhaoxi Sun is supported by the PKU-Boya Postdoctoral Fellowship. We are grateful for many valuable and insightful comments on the performance of different charge schemes from the anonymous reviewers.

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  1. State Key Laboratory of Precision Spectroscopy, School of Physics and Electronic Science, East China Normal University, Shanghai, 200062, China

    Zhe Huai & Zhaoxi Sun

  2. College of Engineering, Hebei Normal University, Shijiazhuang, 050024, China

    Huaiyu Yang

  3. Physics, Engineering, Earth, Environment, Mechanics (PhITEM), University Grenoble Alpes, 38000, Grenoble, France

    Xiao Li

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  1. Zhe Huai
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Huai, Z., Yang, H., Li, X. et al. SAMPL7 TrimerTrip host–guest binding affinities from extensive alchemical and end-point free energy calculations. J Comput Aided Mol Des 35, 117–129 (2021). https://doi.org/10.1007/s10822-020-00351-9

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