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Application of the alchemical transfer and potential of mean force methods to the SAMPL8 host-guest blinded challenge

Journal of Computer-Aided Molecular Design volume 36, pages 63–76 (2022)Cite this article

Abstract

We report the results of our participation in the SAMPL8 GDCC Blind Challenge for host-guest binding affinity predictions. Absolute binding affinity prediction is of central importance to the biophysics of molecular association and pharmaceutical discovery. The blinded SAMPL series have provided an important forum for assessing the reliability of binding free energy methods in an objective way. In this challenge, we employed two binding free energy methods, the newly developed alchemical transfer method (ATM) and the well-established potential of mean force (PMF) physical pathway method, using the same setup and force field model. The calculated binding free energies from the two methods are in excellent quantitative agreement. Importantly, the results from the two methods were also found to agree well with the experimental binding affinities released subsequently, with R values of 0.89 (ATM) and 0.83 (PMF). These results were ranked among the best of the SAMPL8 GDCC challenge and second only to those obtained with the more accurate AMOEBA force field. Interestingly, the two host molecules included in the challenge (TEMOA and TEETOA) displayed distinct binding mechanisms, with TEMOA undergoing a dehydration transition whereas guest binding to TEETOA resulted in the opening of the binding cavity that remains essentially dry during the process. The coupled reorganization and hydration equilibria observed in these systems is a useful prototype for the study of these phenomena often observed in the formation of protein-ligand complexes. Given that the two free energy methods employed here are based on entirely different thermodynamic pathways, the close agreement between the two and their general agreement with the experimental binding free energies are a testament to the high quality and precision achieved by theory and methods. The study provides further validation of the novel ATM binding free energy estimation protocol and paves the way to further extensions of the method to more complex systems.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Notes

  1. http://www.github.com/samplchallenges/SAMPL8/tree/master/host_guest/GDCC.

  2. http://www.github.com/samplchallenges/SAMPL8/blob/master/host_guest/Analysis/ExperimentalMeasurements/Final-Data-Table-031621-SAMPL8.docx.

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Acknowledgements

We acknowledge support from the National Science Foundation (NSF CAREER 1750511 to E.G.) and National Institutes of Health (R01GM100946 to T.K.). Molecular simulations were conducted on the Comet and Expanse GPU clusters at the San Diego Supercomputing Center supported by NSF XSEDE award TG-MCB150001. We appreciate the National Institutes of Health for its support of the SAMPL project via R01GM124270 to David L. Mobley.

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Authors and Affiliations

  1. Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn NY, USA

    Solmaz Azimi, Joe Z. Wu, Sheenam Khuttan & Emilio Gallicchio

  2. PhD Program in Biochemistry, Graduate Center of the City University of New York, New York, NY, USA

    Solmaz Azimi, Sheenam Khuttan, Tom Kurtzman & Emilio Gallicchio

  3. PhD Program in Chemistry, Graduate Center of the City University of New York, New York, NY, USA

    Joe Z. Wu, Tom Kurtzman & Emilio Gallicchio

  4. Department of Chemistry, Lehman College of the City University of New York, Bronx, NY, USA

    Tom Kurtzman

  5. Department of Chemistry and Physical Sciences, Pace University, New York, NY, USA

    Nanjie Deng

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  1. Solmaz Azimi
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Correspondence to Emilio Gallicchio.

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Azimi, S., Wu, J.Z., Khuttan, S. et al. Application of the alchemical transfer and potential of mean force methods to the SAMPL8 host-guest blinded challenge. J Comput Aided Mol Des 36, 63–76 (2022). https://doi.org/10.1007/s10822-021-00437-y

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  • DOI: https://doi.org/10.1007/s10822-021-00437-y

Keywords

  • Binding free energy estimation
  • Computational alchemy
  • Potential of mean force
  • SAMPL
  • Host-guest