In the SAMPL7 host-guest challenge, we ran our reference calculations using an alchemical approach with the YANK auto-225 mated toolkit. With this approach we used the Hamiltonian replica-exchange sampling method , and in some cases we 226 could not achieve convergence in the free energy estimate even with 50 ns of simulation. For SAMPL8 we decided to take an 227 alternative approach employing the APR method via the pAPRika toolkit. The APR method is a physical path-based method using 228 umbrella sampling (US) and has been used in previous SAMPL challenges . We decided to use this approach for several reasons: (a) The use of US in APR allows for each individual and independent umbrella or state to be simulated separately. Thus,