Binding of Homeodomain Proteins to DNA with Hoogsteen Base Pair

In DNA double helices, Hoogsteen (HG) base pairing is an alternative mode of Watson-Crick (WC) base pairing. HG bp has a different hydrogen bonding pattern than WC bp. We investigate here the binding energy of homeodomain proteins with a HG-DNA duplex, where DNA adopts a HG bp in its sequence. We observe that the presence of the HG bp increases the binding energy of both the specific and nonspecific homeodomain proteins compared to WC-DNA bps. The neutral mutation in the N-terminal basic arm of the nonspecific protein significantly changes the binding energy between nonspecific protein and HG-DNA only, while the acidic mutation significantly changes the binding energy of both the specific and nonspecific proteins with HG-DNA. The significant variation in the binding energy of the homeodomains within distinct DNA-protein complexes can be ascribed to the differences in the number of intermolecular contacts between DNA bases and protein residues. Our conformational thermodynamics calculations based on the fluctuation of microscopic conformational variables at the interface show that with increasing conformational stability and order at the interface, the binding of the homeodomain protein gets stronger.