We ended up choosing two protocols, varying in number of lambda windows (with all other simulation parameters kept consistent), with one being for systems with neutral guests and a second for guests with a formal charge. We expected that a second protocol for guests with a formal charge would be needed since electrostatic interactions would be much stronger with its environment and limit sampling. Indeed, after testing the "neutral" protocol on a charged guest we noticed insufficient replica mixing per an issued warning from a generated YANK simulation health report. The protocol for neutral guests had 31 lambda windows and was based on a previous protocol used on -CD with cyclopentanol as the guest. This protocol was tested on -CD with 4-methyl-cyclohexanol as the guest. For systems with a charged guest, we ran a test free energy calculation using YANK's automatic pipeline to determine the best alchemical path (lambda windows and values) based on a -CD and the positively charged rimantadine (g2) guest, resulting in 61 lambda windows. Both of the test calculations were within 4 kcal/mol of experimental values upon completion, and simulation health reports showed reasonable exchange between replicas and exhibited apparently reasonable convergence. However, in the case of the charged guest, convergence was not as convincing at similar time scales. For example, the test calculation for the neutral guest showed reasonable convergence by 14 ns per window while in the case of a charged guest, simulations were run for 26 ns per window and convergence was still not as obvious.