Computer simulation of DNA double-helix dynamics.

The static structure of DNA has been known for 30 years (Watson and Crick 1953). During the past 5 years, DNA has been shown to have a surprising degree of conformational flexibility in that the number of base pairs per turn is not the same in solution and in fibers (Amott and Hukins 1972; Wang 1979; Rhodes and Klug 1980), that the base and backbone atoms undergo angular motions of large amplitude ( > 25”) on a time scale of nanoseconds (Early and Kearns 1979; Bolton and James 1980; Hogan and Jardetsky 1980), and that there are cooperative conformational transitions mediated by changing environment or binding of drug molecules (Sobell et al. 1977; Hogan et al. 1979; Dattagupta and Crothers 198 1). Model building and computer calculations have considered the static deformation of the DNA double helix by kinking (Crick and I$lug 1975; Sobell et al. 1977) or by smooth bending (Levitt 1978; Sussman and Trifonov 1978). Elegant mathematics has been used to analyze the dynamic behavior of DNA by assuming that the molecule behaves l ike an isotropic elast ic rod (Barkley and Zimm 1979). In the study described in this paper, the nature of the dynamics of the DNA double hel ix was invest igated using the technique of molecular dynamics simulation, which proved so illuminating when used on globular proteins (McCammon et al. 1977; Levitt 198lb). This technique s imulates the movement of a toms in the s ta t ic X-ray structure and thus provides information about the amplitudes and frequencies of vibrations and the type, rate, and pathway of conformational changes. Results are presented for simulations of room-temperature atomic motion of 12-bp and 24-bp DNA double helices for periods of more than 90 psec. The hydrogen bonds between base pairs are all found to be stable on this t ime scale, and the motions of the torsion angles are found to be of small ampli tude ( c loo). The length fluctuat ions of adjacent hydrogen bonds in the same base pair are weakly correlated, whereas the torsion angles of each nucleotide show stronger correlations that agree with those seen in the stat ic X-ray structures. Both DNA fragments show cooperat ive overal l bending and twisting motions of large ampli tude that do not involve any major perturbation of the DNA torsion angles. This smooth bending differs from that expected of an isotropic elast ic rod in that (1) i t is asymmetric, always act ing to close the major groove of DNA, and (2) it consists predominantly of a normal mode that has a wavelength close to the helical repeat length. The stack of base pairs is also seen to kink into the minor groove. The extent of this global motion is consistent with nuclear magnetic resonance measurements and explains the observed sensi t ivi ty of DNA conformation to local environment . These calculat ions have implications for the way the DNA double helix may interact with repressors, polymerases, and other cellular proteins (Anderson et al. 198 1; McKay and Steitz 198 1). The marked contrast between the bending flexibility and the stability of the hydrogen-bonded base pairs suggests that DNA may protect the integri ty of the genetic message by absorbing thermal perturbat ions in bending motions, rather than in base-pair-opening motions.