Determinants of the Fe-CO and C-O stretching frequencies in (imidazole)heme-CO adducts have been investigated via density functional theory (DFT) analysis, in connection with puzzling characteristics of the heme sensor protein CooA and of the H-NOX (Heme-Nitric Oxide and/or OXygen binding) family of proteins, including soluble guanylate cyclase (sGC). The computations show that two mechanisms of Fe-histidine bond weakening have opposite effects on the nuFeC/nuCO pattern. Mechanical tension is expected to raise nuFeC with little change in nuCO whereas the weakening of H-bond donation from the imidazole ligand has the opposite effect. Data on CooA indicate imidazole H-bond weakening associated with heme displacement, as part of the activation mechanism. The computations also reveal that protein-induced distortion of the porphyrin ring, a prominent structural feature of the H-NOX protein TtTar4H (Thermoanaerobacter tengcongensis Tar4 protein heme domain), has surprisingly little effect on nuFeC or nuCO. However, another structural feature, strong H-bonding to the propionates, is suggested to account for the weakened back bonding that is evident in sGC. TtTar4H-CO itself has an elevated nuFeC, which is successfully modeled as a compression effect, resulting from steric crowding in the distal pocket. nuFeC/nuCO data, in conjunction with modeling, can provide valuable insight into mechanisms for heme-protein modulation.