So I have not been in the Rosetta world for very long, and most of what I have learned I have had to parse from the Rosetta Commons Demos/Documenation and various publications since no one else at my institution does this sort of work. So while I have learned quite a bit, there is some fundamental questions about approach/methodology that I feel blind towards.
One of the biggest questions I have is about the design of enzyme active sites/ligand binding pockets and their relationship to the underlying backbone. In virtually every publication I have read, the primary way this is done is the creation of a theozyme/theoretical minimal binding interactions, and then using Rosetta Match to place these sidechains onto an existing PDB.
My question is this: can one work without Rosetta Match? Can one design a theozyme or binding pocket, and then de novo design a backbone that can accomodate the necessary interactions? What is the primary benefit to the traditional protocol of matching to an exsting PDB? It would appear at first that designing a completely novel backbone to accomodate the active site might allow more freedom to the designer.
I know this question is more theoretical than the typical question about the software itself, but any guidance on this would help me to develop my understanding of protein design as a whole.