We employed our novel Alchemical Transfer Method (ATM) to compute standard binding free energies of the TEETOA and TEMOA complexes. ATM utilizes an alchemical intermediate state, similar to the notorious Double Decoupling Method (DTM), to link the unbound and bound states of molecular association in the thermodynamic path. At the intermediate state in ATM, the guest interacts simultaneously with the solvent bulk and the binding region of the host at half strength. The intermediate state in DTM on the other hand is defined as the guest in vacuum. In contrast to DTM, ATM is performed in the same solvent box of the thermodynamic cycle, in which the guest does not leave the solvated system.
The excess binding free energy is expressed as the difference of the free energies between the unbound and bound states. In the context of ATM, the unbound state is defined as a configuration in which the guest is in the solvent bulk and the bound state as a configuration in which the guest is in the binding site region of the host. In order to rigidly translate the guest from the binding site of the host and into the solvent environment, a constant translation vector is defined such that a configuration of the bound state maps to a unique configuration in the unbound state. As a result, all the other degrees of freedom of the system remain unchanged.
The alchemical path in ATM is split in two “legs” that represent the bound and unbound end states and their respective hybrid potential energy functions. If lambda = 0 represents the bound state, in which the guest interacts only with the binding site of the host, the alchemical pathway is terminated at lambda = 1/2. If lambda = 1 represents the unbound state, leg 2 connects the unbound state to the intermediate state similarly to leg 1, in which the alchemical pathway is extended up to lambda = 1/2. The binding free energy is expressed as the difference between leg 2 and leg 1 of the alchemical transformation.
Lambda = 1/2 represents the intermediate state of ATM. In this alchemical transformation, the intermediate state is unique such that it represents an ensemble in which the guest has simultaneous and symmetric interactions with not only the binding site of the host, but also the solvent environment. At this intermediate state, the guest interacts with its relative components at half strength and with minimal steric clashes, which preserves the original and soft-core perturbation potentials.
The SAMPL8 GDCC challenge is an excellent context to test ATM, as it allows us to assess not only conformational sampling with regards to sterics nad flexibility, but also protonations states that might be of interest in addressing for binding free energy protocols.
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