The pathways by which small molecules (substrates or inhibitors) access active sites are a key aspect of the function of enzymes and other proteins. A key problem in designing or altering such proteins is to identify sites for mutation that will have the desired effect on the substrate transport properties. While specific access channels have been invoked in the past, molecular simulations suggest that multiple routes are possible, complicating the analysis. This complexity, however, can be captured by a Markov State Model (MSM) of the ligand diffusion process. We have developed a sensitivity analysis of the resulting rate matrix, which identifies the locations where mutations should have the largest effect on the diffusive on rate. We apply this method to myoglobin, which is the best characterized example both from experiment and simulation. We validate the approach by translating the sensitivity parameter obtained from this method into the CO binding rates in myoglobin upon mutation, resulting in a semi-quantitative correlation with experiments. The model is further validated against an explicit simulation for one of the experimental mutants.