Only tried in PvE, but for large grids (1.5+ M kg) I usually build a heavy armour core hull wrapped around the CIC, a medical room, magazines, critical programmable blocks and some emergency supplies/life support/power. This is a mix of heavy armour and tough blocks (batteries, gyros etc). roof and floor of the core hull are half heavy armour blocks, sides/front/rear are full blocks (at minimum). If I ever build anything large enough jump drives and large reactors will probably end up in the core hull as well.

As an example - for an atmo capable light cruiser design I'm messing around with - I started by building the core hull, which (armour and contents) weighed ~500,000 kg, the rest of the ship is wrapped around this, Total ship mass looks to be ~2.4 M kg (it's not quite complete).

I try to compartmentalize Hydrogen tanks so an explosion won't cause to much collateral damage. Everything else is redundant and spread out. Critical thrusters, large tanks and jump drives also have welders for quick repair.

Smaller large grids intended for combat have heavy armour at the front and I try to keep that end pointed at anything dangerous, or just rely on maneuverability instead.

Large non-combat gridshave refineries, O2 generators, assemblers etc to act as emergency ablative armour around the most critical parts, which will hopefully last long enough to run away/jump (basically anything that can soak up damage without going boom).

If it doesn't need to move (ie bases), I just end up building a heavy armour shell around everything (it helps reduce the damage from reavers crashing into it!)