Molecular mechanical studies of DNA flexibility: Coupled backbone torsion angles and base-pair openings

Abstract

Molecular mechanics studies were carried out on B-DNA-like structures of [d(C-G-C-G-A-A-T-T-C-G-C-G)]2 and [d(A)]12.cntdot.[d(T)]12. Each of the backbone torsion angles (.psi., .phi., .omega., .omega.'' .phi.'') was forced to alternative values from the normal B-DNA values (g+, t, g-, g-, t conformations). Compensating torsion angle changes preserve most of the base stacking energy in the double helix. In a 2nd part of the study, one purine N3-pyrimidine N1 distance at a time was forced to a value of 6 .ANG. in an attempt to simulate the base opening motions required to rationalize proton exchange data for DNA. When the 6-.ANG. constraint is removed, many of the structures revert to the normal Watson-Crick H-bonded structure, but a number are trapped in structures .apprxeq. 5 kcal/mol higher in energy than the starting B-DNA structure. The relative energy of these structures, some of which involve a non-Watson-Crick thymine C2(carbonyl).cntdot..cntdot..cntdot..cntdot.adenine 6NH2 H-bond, are qualitatively consistent with the .DELTA.H for a base pair-open state suggested by Mandal et al. of 4-6 kcal/mol. The picture of DNA flexibility emerging from this study depicts the backbone as undergoing rapid motion between local torsional minima on a nanosecond time scale. Backbone motion is mainly localized within a dinucleoside segment and generally not conformationally coupled along the chain or across the base pairs. Base motions are much smaller in magnitude than backbone motions. Base sliding allows imino N.sbd.H exchange, but it is localized, and only a small fraction of the N.sbd.H groups is exposed at any one time. Stacking and H-bonding cause a rigid core of bases in the center of the molecule accounting for the hydrodynamic properties of DNA.