Nowadays it is very much frame dependent, as bottles are taken into account with the aerodynamic design.
On a tradition round tubed bike, it is true to say that a single large bottle on the seat tube is more aerodynamic than two smaller bottles, or a single large bottle on the down tube. Most of the newer aero bikes though have been designed to provide a degree of shielding to a bottle placed on the down tube. For example, the current cervelo s5 and Pinarello f12 are both designed with bottles in mind. On bikes like these, a bottle causes less aerodynamic drag when on the down tube. Most of this design though is based around a single small bottle, so whether a single large bottle on the downtime would be better than two small bottles is more of a question to be answered.
The aerocoach testing is interesting, but they have used a frame that is not really designed to carry any water bottles in the main triangle. It may be the case that a frame that is aero optimised to such an extreme scenario is more negatively impacted by a bottle than a standard road bike would be. Basically, their testing is great but it is completely unrepresentative of the vast majority of road bikes. It would be great to see them replicate the testing with a standard, non aero optimised, bike
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