The effects of the isotopic labeling on the vibrational fingerprint of cysteine were studied computationally using DFT calculations. Two ionic forms were considered: the zwitterion for a free molecule and a cysteine molecule adsorbed onto Ag4 + nanocluster via a deprotonated thiol group. The zwitterion was chosen because cysteine exists in this form in the solid state for which Raman spectrum was collected. Thiolate form of cysteine-Ag4 + system was selected as a simple approximation of the conditions representative of the SERS measurement (which has proven to work well for modeling of SERS spectra of short peptides 92 ). The system as a whole had no net charge and the wavefunction was optimized using a spin-unrestricted algorithm with the multiplicity of 2. Both forms had, at first, their geometries optimized and vibrational wavenumbers calculated for the unlabeled isotopologue (Cys-cabn). The energy and optimized atom coordinates are disclosed in the Supporting Information (Chapter 6) for both forms. All vibrational wavenumbers were real proving the optimization to a local minimum. The vibrational wavenumbers were then recalculated for every combination of carbon and/or nitrogen atoms isotopic labeling at the optimized minimal geometry. The naming scheme was based on upper-or lowercase letters c, a, b, and n representing the heavier or lighter isotopologue of carboxyl, alpha, beta carbon atoms and nitrogen atom, respectively. The scheme is detailed further in Table and illustrated in Fig. of the Supporting Information.