Is it possible to use a protein single state design protocol to increase a protein's affinity towards a ligand? Any suggestions are appreciated.
Yes. There are several ways to accomplish this. One approach is to use the RosettaLigand protocol, and add in a design step. This approach is used by the "Enzyme and protein-small molecule interface design" tutorial from the Meiler Lab RosettaWorkshop. (See http://meilerlab.org/index.php/rosetta-tutorials scroll down to it.) Another approach is to use one of the enzyme design approaches.
These are rather closely related under the hood, and can potentially be combined in more complex protocols, depending on the details of your system and what you're hoping to achieve.