The leadzyme is an in vitro selected ribozyme that contains an asymmetrical 4×2 bulge. It is cleaved by divalent lead ions between nucleotides C6 and G7. Three bases in the bulge, C6, G9, and G24, are conserved. A 1.8 Å crystal structure solved in presence of Mg2+ and Sr2+ shows metal ion binding sites in the bulge and helical regions. Lead cleavage is out‐competed and inhibited by Mg2+ ions. The bulge region of the leadzyme is expected to form different structures under different ionic and pH conditions. A25+ • C6 non‐canonical base pair is expected to form in the bulge and shows two hydrogen bonds in NMR structure and one in the crystal structure. Thermodynamic stability and ion binding of wild type, a control helix, and modifications in the conserved and non‐conserved regions are examined by thermal denaturation experiments. Constructs were denatured in various concentrations of Mg2+ ions and 1 M salt in two different pH conditions. The helix is more stable than the wild type; penalty for breaking the helical structure by insertion of a 4×2 bulge is ~3 kcal/mol. The stability of wild type is not pH dependent. The stability of the modified constructs in high salt conditions varies depending on pH. Several bulge modifications indicate pH dependent Mg2+ stabilization. A detailed analysis of thermodynamic results will be presented. This work was supported by NSF grant, MCB‐0950582 to NG.