A-form conformational motifs in ligand-bound DNA structures

Recognition and biochemical processing of DNA requires that proteins and ot her Ligands are able to distinguish their DNA binding sites from other part s of the molecule. Ln addition to the direct recognition elements embedded in the linear sequence of bases (i.e. hydrogen bonding sites), these molecu lar agents seemingly sense and/or induce an "indirect" conformational respo nse in the DNA base-pairs that facilitates close intermolecular fitting. As part of an effort to decipher this sequence-dependent structural code, we have analyzed the extent of B --> A conformational conversion at individual base-pair steps in protein and drug-bound DNA crystal complexes. We take a dvantage of a novel structural parameter, the position of the phosphorus at om in the dimer reference frame, as well as other documented measures of lo cal helical structure, e.g. torsion angles, base-pair step parameters. Our analysis pinpoints ligand-induced conformational changes that are difficult to detect from the global per spective used in other studies of DNA struct ure. The collective data provide new structural details on the conformation al pathway connecting A and B-form DNA and illustrate how both proteins and drugs take advantage of the intrinsic conformational mechanics of the doub le helix. Significantly, the base-pair steps which exhibit pure A-DNA confo rmations in the crystal complexes follow the scale of A-forming tendencies exhibited by synthetic oligonucleotides in solution and the known polymorph ism of synthetic DNA fibers. Moreover, most crystallographic examples of co mplete B-to-A deformations occur in complexes of DNA with enzymes that perf orm cutting or sealing operations at the (O3'-P) phosphodiester linkage. Th e B --> A transformation selectively exposes sugar-phosphate atoms, such as the 3'-oxygen atom, ordinarily buried within the chain backbone for enzyma tic attack. The forced remodeling of DNA to the A-form also provides a mech anism for smoothly bending the double helix, for controlling the widths of the major and minor grooves, and for accessing the minor groove edges of in dividual base-pairs. (C) 2000 Academic Press.