Looking for a program to 'firewall' rarely used folders?

I posted this in the malware section originally, but will repeat here per request:

I recently had a malware problem on my desktop (maybe I still do). Not sure what exactly was behind it, but I finally got my Virus- and Firewall programs back after something disabled them and prevented me from updating and scanning with malware programs I had. It even removed/disappeared new programs I tried to import and install. But I think I finally killed them (mostly a bunch of Trojans).

Anyway, I'm doing thorough virus scans now and they are taking too long because the scanners check all folders. I'd love a program to 'lock away' folders I don't use frequently, sort of like a firewall on full protect. If nothing goes in, surely there would be no need for malware tools to check it. For example, I have Matlab installed because I used to use it, but haven't in the past few years. I'd like to lock it for the time being (read-only), so that nothing would go in and my malware scans/tools could ignore it. Is this possible?
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Perhaps a more elegant solution would be to have your virus scans exclude certain directories? Most apps provide a feature like this. We could provide specific instructions if you were to post what AV you are using to scan with. (Assuming this is a viable solution in your eyes)

 

Yes, that's the idea, I just need a program to guard these folders between scans so I know it's safe to exclude them. I'm looking for a program that can take a snapshot of selected areas, and then at a later time tell me if there have been any changes to these areas, what changed, and perhaps even prompt me if something tries to sneak into them...