Yes, a big opening will allow more air to escape. Regardless, if the interior pressure is raised to .5 inches of air column, you will see bubbles when you spray the soapy water on the exterior.
You're free to tape up any and all air escape routes, it makes it easier to raise the interior pressure.
What I now do is cover the roof vents from inside, put stoppers in the sink and shower, but I don't fuss with the heater flue. That is a 3" pipe and is open to the exterior. I'm able to raise the pressure beyond 1" of water column so no other methods of sealing are necessary. There is a lot of air coming out the door opening when closed as it is a poorly fitted door. I have plans to make that better.