DraStic

Hotel dusk has compatibility issues whenever the frameskip is any different than 0.

Clicking on objects for interactions is buggy whenever the frameskip is higher, maybe it has to do with the way pen presses are dealt with on skipped frames?

Is anyone else experiencing that problem?

Yes, some games need frameskip off to work correctly, because the game reads back the frame data. Hotel Dusk and its sequel Last Window are two examples. It's probably not that common beyond those.