Nuance in the double-helix and its role in protein-DNA recognition

Abstract

It has been known for some time that the double-helix is not a uniform structure but rather exhibits sequence-specific variations that, combined with base-specific intermolecular interactions, offer the possibility of numerous modes of protein-DNA recognition. All-atom simulations have revealed mechanistic insights into the structural and energetic basis of various recognition mechanisms for a number of protein-DNA complexes while coarser grained simulations have begun to provide an understanding of the function of larger assemblies. Molecular simulations have also been applied to the prediction of transcription factor binding sites, while empirical approaches have been developed to predict nucleosome positioning. Studies that combine and integrate experimental, statistical and computational data offer the promise of rapid advances in our understanding of protein-DNA recognition mechanisms.

Figure 1

Histogram of number of released crystal structures of Protein-DNA complexes and free DNA organized by Protein Data Bank release date

Figure 2. Sequence-dependence of minor groove shape for Dickerson dodecamer

– Ideal B-DNA (A) and the Dickerson dodecamer, PDB code 1duf (B), differ in minor groove shape as shown by the color coding of the molecular surface (green for convex, black/grey for concave surfaces). (C) The intrinsically narrow minor groove in the center of the Dickerson dodecamer is predicted by MC simulations using ideal B-DNA as a starting conformation. The X-ray data represent an average of the 15 available crystal structures, symmetrized based on the palindromic sequence CGCGAATTCGCG in order to remove crystal packing effects. The NMR data represent an average of 10 structures that included dipolar coupling data in their structure determination. Minor groove width is calculated with the CURVES program [55].

Figure 3. Recognition of minor grove shape and electrostatic potential by a Hox homeodomain

- Crystal structures of Scr bound to its specific fkh250 sequence, PDB code 2r5z (A), and the Hox consensus sequence fkh250^con*, PDB code 2r5y (B). Color coding of the molecular surface reveals, for the fkh250 site, an extended region with a narrow minor groove, which binds His-12, Arg3, and Arg5. In contrast, the minor groove of the fkh250^con* site is only narrow at the local region that binds Arg5. A mesh of the -8kT/e isosurface illustrates that the electrostatic potential, as calculated with DelPhi [35], is more negative in the minor groove of the fkh250 site than in the fkh250^con* site. MC simulations of the free binding sites indicate the distinct minor groove shape to be an intrinsic feature of the free binding sites (see text). Molecular shape and electrostatic isosurface representations were generated with GRASP2 [56].