Determining Free-Energy Differences Through Variationally Derived Intermediates [component]

Free-energy calculations based on atomistic Hamiltonians and sampling are key to a first-principles understanding of biomolecular processes, material properties, and macromolecular chemistry. Here, we generalize the free-energy perturbation method and derive nonlinear Hamiltonian transformation sequences yielding free-energy estimates with minimal mean squared error with respect to the exact values. Our variational approach applies to finite sampling and holds for any finite number of
more » ... te states. We show that our sequences are also optimal for the Bennett acceptance ratio (BAR) method, thereby generalizing BAR to small sampling sizes and non-Gaussian error distributions.
doi:10.1021/acs.jctc.0c00106.s001 fatcat:6d4t2jhylvdbxgjfbwe5nseega