Exchange 2016 does not work through F5, manually configured.

Probably the easiest way to look at this would be to deploy the iApp and see how the iApp's configuration differs from your manually configured setup (please verify that the iApp is working before comparing). You can contact F5 support and they will help you, but they will also tell you that the only supported way to do this is through the iApp.

But yes, understanding how things are breaking would be helpful.