I find that a lot of console oriented games (which uses four controls buttons in addition to the keyboard) works nice with a multi-button mouse.
For AC2 specifically I have bound the high-profile to a button on the left of my mouse, legs to right-click, main hand to normal click, and off-hand* to wheel-click. **Head can be fairly affected to the keyboard as it is not of so much use.
This has the advantage of requiring me to concentrate on the movement keys on the keyboard (basically going forward, sometimes left and right movement) while having both high-profile and leg buttons pressed on the mouse. These buttons enable me to keep a nice grip and control over the mouse whenever I run.
For other games, I usually bind crouch, run, jump and other action on the keyboard. But usually they are not key you need to hold to much longer like in AC2, thus you don't have to worry about coordination too much or ghosting problems. But usually those games provides a better interface for customisation unlike AC-serie that enable you to customise 4 buttons and derive combinations with these.