Helix α1 of human ACE2 mimics dsDNA and Spike of SARS-CoV-2 binds DNA.

DNA mimicking proteins (DMPs) play regulatory roles in restriction-modification system, transcription, chromatin regulation and DNA repair. DMPs mimic the local shape and charge distribution of backbone of DNA. Conversely, DNA aptamers provide spatial distribution of chemical groups of a protein surface. In either case, integration of shape-complementarity and chemical group distribution is determined by both the sequence of their building blocks and the local shape, thus compounding their identification and design. In this context, we report that helix α1 (Ser19-Asn53) of human angiotensin-converting enzyme 2 (ACE2) and DNA-mimicking helix of Neisseria DMP19 are structurally superimposable. Further, the ACE2-interacting surface of SARS-CoV-2 Spike protein (Ala475-Pro507) structurally aligns with the dsDNA-binding region (Lys9-Arg33) of CREN7 of Sulfolobus. Corroborating the shape and chemical similarity of helix α1 of ACE2 with a dsDNA, certain stem-loop DNA (SL) inhibit ACE2-Spike interaction-based transduction. Docking of these SL to Spike protein reiterates that formation of a stable protein-DNA complex is a combined effect of the local shape of dsDNA, the orientation of side chain of interacting amino acids and their flexibility for an induced-fit. The results described here emphasize that the spatio-chemical similarity between protein and DNA which is a combined effect of sequence and local shape, should be considered for designing aptamer-based antiviral therapeutics.