I have a few games saved with each specialized in one field. One in melee which uses Knock Knock the named Axe from Camp Searchlight's firestation, which is a 1 hit kill, and has a unique VATS attack that knocks someone down if they survive. One in Unarmed which uses the Ballistic Glove, or the Golden Gloves, which knocks out all insects in 3 hits, people in 4, deathclaws in about 10. Energy weapons has me using the YCS-182 named gauss rifle, which is great.
All in all, if you upgrade yourself to a high enough level in that skill, you won't be able to die. In my unarmed playthrough, I wanted to make the game as difficult as possible, so I set the game to very hard and hardcore. Within 4 levels, I had ~100 unarmed and I killed people in a single hit. It doesn't help that, once you reach 45 melee and 45 unarmed, you can get piercing strike, which negates 15DT on the enemy, basically breaking the game from all difficulty other than deathclaws. Getting another skill that has a chance to knock someone over with unarmed ruins fights with deathclaws, as well.
Not to mention that these perks also affect companions, so Veronica and Rex both negate 15DT and knock people over constantly. I seldom get a chance to even punch anymore before Rex takes them out first.