The Protobuild definition files describe your projects; they don't change the invocation of Protobuild, but instead change what it generates.
When you open Protobuild Manager, it should generate the projects, and then open up Visual Studio. While you're working in Visual Studio, leave Protobuild Manager open.
When you're done or before you want to commit to your repository, hit Save All in Visual Studio. Then in the Protobuild Manager click the "Sync Now" button. That will save the changes back to definition files. Whenever you open Protobuild Manager it will generate by default, so if you forget to hit Sync Now after saving changes in Visual Studio or before closing Protobuild Manager, just double-click Protobuild.exe in the project folder instead and that will resync by default. It's then safe to open up Protobuild Manager again.
--resync advice applies if you are running Protobuild from the command line.