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We report the results of our participation in the SAMPL8 GDCC Blind Challengefor host-guest binding affinity predictions. Absolute binding affinityprediction is of central importance to the biophysics of molecular associationand pharmaceutical discovery. The blinded SAMPL series have provided animportant forum for assessing the reliability of binding free energy methods inan objective way. In this blinded challenge, we employed two binding freeenergy methods, the newly developed alchemical transfer method (ATM) and thewell-established potential of mean force (PMF) physical pathway method, usingthe same setup and force field model. The calculated binding free energies fromthe two methods are in excellent quantitative agreement. Importantly, theresults from the two methods were also found to agree well with theexperimental binding affinities released subsequently, with an $R^2$ of 0.89(ATM) and 0.83 (PMF). Given that the two free energy methods are based onentirely different thermodynamic pathways, the close agreement between theresults from the two methods and their general agreement with the experimentalbinding free energies are a testament to the high quality achieved by theoryand methods. The study provides further validation of the novel ATM bindingfree energy estimation protocol and it paves the way to further extensions ofthe method to more complex systems.

Application of the Alchemical Transfer and Potential of Mean Force Methods to the SAMPL8 Host-Guest Blinded Challenge