I put the game on SSD. Even then, loading in/out of areas is painful, so HDD...? Maybe even worse.
Learn to mod. It's not so bad actually with mod installers. Really improve the experience. E.g. I use a custom launcher that gives me 110 FOV. Simple thing, but much better experience.
Use inventory filters (weapons, apparel, aid...) when trading / scrapping. Raw foods not that useful, I pretty much use stimpacks exclusively, although cooking is best.
I have my money for ammo, and special armor and weapons (last minute, spray'n pray, ...). Buying stimpacks and drugs a bit of a waste. Plenty to loot around.
They don't explain the interface much, so if you need a 'how to', look it up. The game is full of hidden or obfuscated shortcuts (like weapon / item shortcuts).
Save constantly, quicksave is F5, as much as you can bear. Bit lame, but otherwise can be frustrating.
Don't shoot everything, and you can run away from most things.
I find it better to specialise in 'utilities' at first. Charisma for special dialogues, hacking and lockpicking, armor crafting and weapons crafting, and later, science (intelligence). There are some low level skills that can help accelerate things (xp, and amount of loot). Makes a weak combat character, but better 'rpg' experience. Look for build recommendations on YouTube. Not easy, limited number of skill points to start with. Decide what you wnat to prioritise. A **** that just pummel things (Grognack!), a more dialogue-oriented RPG, and/or exploration. If you gonna play melee, best play a junky too, with Armor crafting. Look for perk Requirements to setup your attributes. This is pretty much locked once you commit, so watch out. I went charisma, Intel, and agility for critical.
VATS is OK, straight up combat more fun. I mostly use vats to shoot grenades mid-air. If you see a grenade indicator pop up, either do that, but mostly run. Npc's have godlike grenade accuracy. And stay away from burning cars.
Base building not essential. It can be fun, but 'needy'.
Ammo is a pain. .38 is the most common (pipe weapons), 308 is much better. Look everywhere, especially for fusion cores. Power Armor can help you get past most things.
When you buy / sell, vendors only have a limited amount of money, so add some of your junk in the bargain to balance it out.
Ammo, ammo ammo again. You can go through the stuff real quick.
So much stuff in that game. Stay focused, it's easy to get distracted, but can be a lot of fun sometimes (pitch battles between raiders and super mutants, random BOS assault, ...).
I was wondering if there are any tips/must knows which would be handy knowing straight from the start 
