Do you find any errors in the SmarterMail logging referencing corrupt or missing/unreadable GRP files? We have seen instances in the past where a corrupted GRP file causes an email client to continually request the file contents again and again, never quite completing the request, and this will lead to increased resource usage as the server contends with those requests. Slower disks would likely contribute further to this as well, so you may be able to confirm by watching disk queues before/during/after those events as well.
For resource issues I typically recommend setting up a monitoring system like PRTG and configuring it to monitor as many data points as possible for a little while including .NET application pool counters so I can monitor the environment conditions even when Windows has become unresponsive itself. This will allow you to track other data points like connection counts, disk queues, etc which makes putting a picture together a lot easier.
Let us know what you find out and we'll be happy to help point you in the right direction :)
Kyle Kerst
Lead Internal Network/System Administrator
SmarterTools Inc.
smartertools.com