We recently introduced the focused confinement method (FCM), a reaction coordinate-free simulation approach for the calculation of conformational free energy differences in explicit solvent. The method uses reference states for the conformations of interest, partitions the solute into conformationally active and inactive regions, and requires the calculation of desolvation free energies of heavily rigidified mixed harmonic-anharmonic states as part of its procedure. The reference states and partitioning affect the speed of convergence of FCM's constituent simulations in opposing manners, but in the thermodynamic limit have no effect on calculated conformational free energy differences. To aid fast convergence of large systems, a general procedure to quickly partition and construct reference states is introduced. With this, two sets of reference states and associated partitionings were constructed for the closed and open conformation of triosephosphate isomerase (TIM). Despite TIM's size, highly converged desolvation free energies were readily obtained from standard free energy perturbation simulations, due to the fact that the mixed harmonic-anharmonic states are heavily rigidified. FCM calculated free energy differences for loop closing matched the experimental value for both reference sets. The insensitivity to reference states and associated partitioning favors reference states that merely reflect main structural differences, for which convergence is faster. The calculations demonstrate the accuracy and robustness of FCM for large systems, while showcasing its efficiency and ease of use.

Calculation of conformational free energies of large solvated systems with the focused confinement method

ACS Fall 2020 Virtual Meeting

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