A new topological method is presented to generate the isomer structures of compound clusters with well defined covalent bonds. This method, combined with density functional theory, has been used to perform global optimization of (TiO2)n (n = 1–6) clusters. Our comprehensive search not only reproduces all of the known lowest‐energy structures reported in previous works but also reveals some new low‐energy structures. Some energetically unfavorable motifs that induce energy penalties are obtained and discussed. Based on the ground state structures of the anionic (TiO2)n. clusters, the electron affinities and photoelectron spectra are simulated and compared with available experimental data. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011