A Computational Study of the Dissociation of CaS Nanoclusters in the Extracellular Fluid of Cancer Cells: the Effect of pH in the Structure and Stability of Protonated CaS Nanoclusters

Abstract

The acidic pH found in the extracellular fluid of many cancer tumors is an important difference from the slightly basic pH found in the corresponding benign cells. Contrary to common anti‐cancer drugs that have significant side effects in healthy cells, calcium sulfide (CaS) nanoclusters have shown to induce apoptosis selectively in human lung, skin, and breast cancer cell lines in vitro. We hypothesize that CaS nanostructures selectively dissociate in the characteristic acidic extracellular environments of cancer cells into free Ca2+ ions and sulfides such as H2S, HS‐ and S2‐, which can be proved via bench and computational experiments. Theoretical calculations at the DFT/B3LYP/DGVZVP level of theory of bare and protonated (CaS)n clusters (n = 1 to 4) were performed to address this hypothesis using the Gaussian 16W and GaussView 6.0.16 programs by varying the number of protons in a CaS cluster to assess cluster stability and reaction pathways in both acidic and neutral media. The total cluster energy decreases with the number of monomer units (n) in the (CaS)n clusters. The CaS monomer and dimer are more stable in water than in their corresponding standard state by about 336kJ/mol and 390kJ/mol, respectively. A single protonation of a sulfur atom in the solvated monomer results in an increase in the Ca‐S bond length from 2.55Å to 2.73Å, indicative of increasing drive to dissociate. It requires protonation of a sulfur atom by two hydrogen atoms to dissociate the cluster into free Ca2+ and H2S. Water facilitates the dissociation of the clusters when the sulfur atom is bonded by two protons. The products of the reaction of the solvated (CaSH2)2+ is more stable than the corresponding gas phase cluster ion by a significant 1479 kJ/mole. These results are consistent with the dissociation of CaS clusters to free Ca2+ and H2S in acidic media like the one found in the extracellular fluid of malignant tumors. Ca2+ ions are known to cause cell damage in cytosolic concentrations higher than 500nM. The biochemistry of H2S is still under study by several groups worldwide but it is generally accepted that it can be genotoxic and induce apoptosis. Therefore, CaS nanoclusters are promising drugs to selectively inhibit malignant tumor growth with little impact on benign tissue. The results are discussed in terms of the basic requirements of a (CaS)n‐based formulation for cancer treatment.