Non-equilibrium free energy calculations can be used to obtain equilibrium free energy differences from non-equilibrium work distributions, via the Jarzynski or Crooks formalisms. Our work focuses on exploring whether these can potentially provide benefits relative to more traditional equilibrium free energy methods. More specifically, we are focusing on applying alchemical non-equilibrium free energy calculations to account for the presence of multiple potential binding modes. I will discuss how we use a thermodynamic cycle to calculate absolute binding free energies of potential poses identified by docking plus short MD simulation. First, restraints are turned on in order to keep the ligand in the binding site while turning off its interactions in the following step by fast non-equilibrium transitions. After turning these restraints off again analytically, the free energy difference of turning on the interactions of the ligand in solution is calculated.  For the systems studied so far, this approach seems to yield reasonable binding free energies at lower computational costs than equilibrium free energy methods. Since in drug discovery the binding mode of an idea compound is often not known, non-equilibrium free energy calculations can be used as an efficient way to account for the presence of multiple potential binding modes. Especially in fragment-based drug design, where low affinity binding can make crystallographic determination of the binding mode difficult, the application of this method seems to be a promising approach.

Evaluation of alchemical non-equilibrium free energy calculations

2019 Fall National Meeting

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