Up to around level 50 or so, mobs are squishy enough that you don’t need weapons perks at all. Eventually, some super mutants become bullet sponges, and you’ll want some kind of damage boost, either weapon perks or just taking lots of combat drugs as needed.

I like to start new games with a focus on Science and Barter. With one point of Science, you can build Industrial Water Purifiers in your settlements. The excess water they produce can be sold to vendors.

Unique leg armor that increases your movement speed can be purchased in Goodneighbor and Vault 81. The Vault 81 vendor also sells the last gun you’ll ever need. I like to trade water for those ASAP.

Next, there’s a quest from The Railroad that gives a HUGE defensive boost.

The Nukaworld expansion introduced a new kind of knife, the Disciples Blade, and it is by far the best melee weapon in the game. A sneaky ninja melee build wielding a Disciples Blade can beat every encounter. The build doesn’t really blossom until the late-late game, but once it does, you’ll never need to use a gun again.