Quantum chemical studies of biologically relevant copper thiolate clusters can afford unique information about energetic principles of their formation and structure, which is important for understanding the basic principles of their formation and functioning in biological systems. In the current study, we used quantum chemical methods for the investigation of the structure and stability of CuxSy-type clusters that serve as models for different copper thiolate clusters or for their intermediates in a variety of copper proteins. Density functional theory based modeling was performed including solvent effects for water and protein-like environments. Thermodynamic parameters (Delta H, Delta S, Delta G) were calculated in order to assess the effect of thermal contributions to the formation energies of various copper thiolate clusters. The all-tricoordinated polycopper thiolate cluster [Cu-4(SMe)(6)](2-) turned out to be the most stable structure among the calculated ones. This result is in agreement with the prevalence of this type of clusters in various copper proteins with no sequence homology that contain six cysteine residues. The cooperativity of formation of [Cu-4(SMe)(6)](2-) can be inferred from the significant energy differences between intermediary clusters. Among tetrathiolate structures, [Cu-4(SMe)(4)](2-) was the most stable one. This cluster is also found in many copper proteins. Influence of slight Structural perturbations on the energetics of copper thiolate clusters is also analyzed and discussed.