The folding and stability of G-quadruplexes (Gq) are correlated with cancer and depend significantly on the chemical environment. Crowders are an important constituent of living cells. However, an understanding of the folding and topology of Gq induced exclusively by a crowder is lacking. Hence, folding and stabilization of the human telomere (htel) induced by polyethylene glycol and its derivative crowders have been studied using different biophysical techniques without the addition of salt. The data suggest that the crowder can alone induce the folding of the htel sequence into Gq and the topology of the folded structure depends on the composition of the crowder. Interestingly, a small chain size crowder favors the folding of the htel duplex to Gq, whereas a larger crowder prefers to stabilize the duplex form. Thermochemical data suggest that the nonlinear trend of the stability of folded Gq is modulated mainly by hydrogen bonding between the flexible part of the crowder and nucleobases, and the role of the excluded volume is not prominent. These findings might play an important role in improving our understanding of the folding and stabilization of htel in complex bimolecular environments.
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