One of my favorite games, probably put in 400 hours into vanilla goty version. I agree with most of the stuff posters above wrote! Here's some tips:
In the workshop or in your pip-boy you can mark specific materials and then in the world during looting a little magnifying glass icon will show up next to an item if it has the material you want. (e.g you marked adhesive so a duct tape item will have that icon) Makes it easier to only pick up and find junk items that have the materials you want for crafting weapons for example.
Everything in your settlement is safe storage so it won;t despawn and you can safely put everything in the workshop it has nearly unlimited capacity.
You mentioned speech checks, you can quicksave even in the middle of the conversation so you can easily save-scum and reload if you fail one.
Settlements were a fun part of the game for me, but if you don't care about them then you can absolutely skip them, it's just an optional part of the game. There is a small quest in the main story with settlements but luckily the game will give you everything you need. There's a couple of settlement spots near rivers or sea that can be used as an insane money maker but that's more for end-game. The trick is to basically put as many water purifiers as you can, some turrets to defend them and empty the workshop. This will produce a ton of purified water which sells for some nice amount of caps. I had tens of thousands of caps every few hours with this method. Money isn't so hard to come by in this game but It was nice not having to worry about caps. I don't know if this was patched or not, it shouldn't since it's not a glitch, it's just using game systems to your advantage but it's probably the best method for money farming.
One of the best perks that can make the game a lot easier the further you're in are those that increase weapon damage, there's like 3 or 4 different ones that add 20,40,60% and so on to base dmg of a weapon type depending on the perk. There's one for pistols, non-automatic, automatics and something else.
The other essential perks are those for hacking and lockpicking since they will give you access to more resources and make exploration easier. Also there's no level cap so you can get every skill and perk there is but that takes a ton of time, likely hundreds of hours but there's no real way of making bad decisions so don't worry to much when picking perks.
F4 has a layer armour system. There are certain pieces of clothing, like your vault suit for example, that you can put other pieces of armor over. I pretty much often played through the game with my vault suit as the base and switched to different armor pieces as the game progresses so vault suit + leather armor set/metal and so on.
Other than that, just play however you want, there's no right or wrong way to play. The game has both fixed lvls for creatures and scaling. The further south you go on the map the stronger the enemies and every 9-10 or so levels the enemy type will change in order to scale a bit to your level (so on lvl 1 you might meet a raider newbie let's call him and on lvl 20 you might meet raider veteran and so on)
And final note, you can change the difficulty at any time, even in the middle of combat. Difficulty however affects the spawn chances of so-called "legendary enemies" with a star next to their name that drop random special loot, for example a weapon that needs no reloading, armor piece that adds to your stats and plenty other random useful or just silly modifiers. On the easiest they can still spawn but the higher the difficulty the more chances such creature variants will spawn.
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