Simonstown is great, if a little quiet. You are on a main commuter train route into Cape Town itself, and it is less than an hour by car depending on traffic and time of day. As a base it puts you within easy reach of Cape point, and areas such as Kalk bay, Fishhoek etc - all of which are pleasant.
I love Cape Town and the surrounding areas - I studied there for 3 years during the early 1980s, and my parents now live there. A lot depends on what you want to see and do. Simonstown is a fair way from the winelands.
As far as safaris are concerned, look at the Kruger National Park - there is a good national parks site
Here.Flying up to the vicinity of the park, and hiring a car from somewhere like Nelspruit would be quite easy. The park is huge (Bigger than Wales) and has huge amounts of animals, but also good quality accomodation, and good roads.
Other things you might consider are moving along the Garden Route between Cape Town and Port Elizabeth. There are numerous places to stay and sights along that stretch of the coast. I really like Storms River , Tsitsikamma and Knysna.
I am not a great fan of Johannesburg and Guateng, although I lived there for several years. Parts of Kwazulu - Natal are lovely, but I have only ever visited briefly.
TimW