Multiple applications not responding, will not shut down

Greetings,
I own a mini from late 2007, 2 ghz model running 10.5.8.
Recently I started running into problems running ProTools 7.3.1 and plugins. The machine had a lot of different software on it, probably too much for its own good. So I decided to do a clean install. After the install I re-installed only ProTools, its plug ins, and a couple of other useful applications. Everything seemed to work well for the first week, and then yesterday I started noticing that programs were not responding. It seemed as though every single program that I tried to use would hang indefinitely and then resist force quitting. It would even happen to finder, and upon relaunching it the same things would start to happen. Restarting the machine made no difference. The hanging programs would actually not allow me to properly shut the machine down, so I had to hard boot it with the power button. This continued for 4 or 5 restarts, then I gave up on it.
Has anyone had a similar issue in the past? I am not sure what could be causing the problems.

So I unplugged all peripherals besides the keyboard, mouse and monitor. I ran some applications, open and closed some things, moved back and forth between programs, no problems whatsoever. Then I plugged my ProTools MBox back in, ran a ProTools session, saved things and closed it, also with no problems. I gave it a fresh restart just for the **** of it.
Everything seems to be working. I think that the problem may be the 1 terabyte external drive I had plugged into it. It's got about 430gb left of space on it. In the past I had a different drive that was 320gb, which burnt out on me after a while.
I used to work on files directly on the external drive, but I think I will stop doing that in order to preserve its functionality.

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