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Understanding the role of non‐Watson‐Crick base pairs in DNA–protein recognition: Structural and energetic aspects using crystallographic database analysis and quantum chemical calculation

Specific recognition of DNA base sequences by proteins is vital for life‐cycles of all organisms. In a large number of crystal structures of protein–DNA complexes, DNA conformation significantly deviates from the canonical B‐DNA structure. A key question is whether such alternate conformations exist prior to protein binding and one is selected for complexation or the structure observed is induced by protein binding. Non‐canonical base pairs, such as Hoogsteen base pairs, are often observed in crystal structures of protein–DNA complexes. We decided to explore whether the occurrence of such non‐canonical base pairs in protein–DNA complexes is induced by the protein or is selected from pre‐existing conformations. Detailed quantum chemical calculations with dispersion‐corrected density functional theory (DFT‐D) indicated that most of the non‐canonical base pairs with DNA bases are stable even in the absence of the interacting amino acids. However, the G:G Hoogsteen base pair, which also appears in the telomere structure, appears to be unstable in the absence of other stabilizing agents, such as positively charged amino acids. Thus, the stability of many of the non‐canonical base pair containing duplexes may be close to the canonical B‐DNA structure and hence energetically accessible in the ground state; suggesting that the selection from pre‐existing conformations may be an important mechanism for observed non‐canonical base pairs in protein–DNA complexes.