Computer simulation of protein-induced structural changes in closed circular DNA.

The effect of protein-induced wrapping on overall DNA folding is studied using Monte Carlo computer simulation techniques. A new modeling scheme is devised to represent configurations of closed circular DNA containing fragments of the double helix partially wrapped around a core of proteins. The DNA consists of two regions, a fragment wrapped in a left-handed superhelical path around a 'phantom' protein core and a free connecting loop. The loop has at least one single-stranded scission so that it can assume a torsionally relaxed state. The configuration of the loop is varied during the course of the computer simulations and the three-dimensional spatial arrangements of lowest total energy are identified. The axis of the DNA loop is represented by a finite three-dimensional Fourier series perturbation of an initial Bézier curve, making it possible to fix the position and orientation of the chain ends as well as the contour length of the free loop. The energy is approximated by elastic terms for the bending and twisting of the DNA and an excluded volume contribution that prevents the self-intersection of sequentially distant chain segments. The proportions of the protein-DNA complex, the number of superhelical turns, the chain length and the imposed linking number difference of the closed DNA are varied in the calculations. The resulting minimum energy structures are consistent with physical models and suggest new ways to think about how proteins add and remove supercoils from DNA. Of special note in this regard is the sudden collapse of three-dimensional structure that accompanies small incremental wrapping of the DNA around the idealized protein core. These observations offer new structural insight into the mechanisms of action of proteins which add or remove supercoils from DNA and provide a first step in thinking about the activity of such systems at the chemical level whereby small fluctuations in local molecular structure are translated into large-scale macromolecular changes. The configurations identified in the simulations can also be examined in the context of the well known "linking number paradox" associated with nucleosome formation on closed circular plasmids. The findings bear relevance to DNA with natural curvature as well as to protein-induced bending and deformations of the double helix.