OK I have to say I completely regret not having a 100 in at least lockpicking or science. There have been a ton of cases where it would have helped. I do think a 100 lockpick is best. If I did this game again I would certainly go for that and possibly shortchange medicine. Other than requiring a 60 to rescucitate somebody, it only otherwise makes stimpaks and what not more effective, but that's just money. Maybe I'd go less on sneak, but having only a 77 science and 25 lockpick sucks! I also wouldn't have gotten the perk that gives a 10% experience bump, it's useless with the top level-cap of 20.
I have received a couple of plasmas now. I cannot say for sure whether big guns or laser is best since I've not used my plasma yet or the gatling laser.
BTW I had three lockups a couple days ago. In VATS with the railroad rifle in the subway tunnel near tenpenny it locked up each time I'd hit a ghoul. My xbox was on a hot cable box source (it's a jasper but it was hot) so I don't know if it was that or the ghouls. I am thinking probably the ghouls and rifle, since it happened only during vats, but in any case now the xbox is by itself. Also, leaving rivet city's market when I was told it was about to close dogmeat and charon didn't join me, then I couldn't get back in because it was locked. I had to wait until morning, then I could go back in and retrieve them.
I'm now running from the HD and load times are indeed better.