Julie,
My guess is the negative pressure and smaller pipe sizes are a result of you closing things off and trying to isolate and size each section. The system couldn't see the big picture so it just sized portions based on the flows it saw in each section.

This is definitely a large site, and very complex to boot. I see nothing wrong with how things are setup only to say with as many Valve-in-head rotors you have, with so many main and sub loops, this would tax any system. I actually loaded up and started sizing things yesterday and let the system chug over night to see how it went with everything open. I am still on preparing 555 valves of 1393! So yes, I might suggest a few things here.

Primarily I would break this down into a much simpler shell, and try splitting things into different files (same project). I would start with a file that held the overall mainline loops, and where you tee into each of the sub-loops (after each of the shut-off valves) I would place a system monitor (if you would like to see what you have available at each of these points) or a Cap (if you know the demand you would like to have at each of these points). Doing this will drastically reduce the amount of path calculations currently happening for every single VIH rotor. I am positive you would see differences in sizing and pressures since you will be able to do the entire system, not just portions.

The second file could be your VIH placements with all sub-loops piped. But instead of going back out through the main loops and back to the POC, you could create separate POC's that started at each of the Caps/System Monitors you placed. The performance data you would tie to each POC would be the corresponding data that you put to that locations Cap/System Monitor, which would essentially be like a continuation of what you did in your first file, allowing you to size each POC from there. You could then XREF your first file into the second so they looked connected.

I would definitely try that, as I think you will get quicker results, allowing you to play with different setups until you get the outcome you are looking for. I would also love to hear from the masses about anything else they are doing on such large jobs!

I hope this helps, but feel free to reach out for anything else.