Modeling protein-induced configurational changes in DNA minicircles

Abstract

A method is offered for obtaining minimum energy configurations of DNA minicircles constrained by one or more DNA‐binding proteins. The minicircles are modeled as elastic rods, while the presence of bound protein is implied by rigidly fixing portions of these chains. The configurations of the geometrically constrained circular rods are sampled stochastically and optimized according to a simple elastic energy model of nicked DNA. The shapes of the minimum energy structures identified after a simulated annealing process are analyzed in terms of relative protein orientation and writhing number. The procedure is applied to minicircles 500 base pairs in length, bound to two evenly spaced DNA‐wrapping proteins. The presence of histone octamers is suggested by rigidly fixing the two protein‐bound portions of each minicircle as small superhelices similar in dimension to nucleosomal DNA. The folded minimum energy forms of sample chains with different degrees of protein wrapping are noteworthy in themselves in that they offer a new resolution to the well‐known minichromosome linking number paradox and point to future minicircle simulations of possible import. © 1997 John Wiley & Sons, Inc.

Modeling Chain Folding in Protein-Constrained Circular DNA

“…In addition, the optimized configurations of the smallest rings shed light on the topological changes witnessed for comparably sized experimental systems analyzed by gel electrophoresis (Zivanovic et al, 1988). The present structures also confirm previous findings (Martino and Olson, 1997) on the nonadditivity of a popular geometric descriptor of chain folding, the writhing number.…”

“…Finally, to span a portion of the different sizes of DNA rings utilized in physical minichromosome manipulations, rings of 359 and 500 bp have been optimized. From the minimal energy structures obtained with the present algorithm, it is clear that ring size and nucleosome spacing are significant configuration-defining variables, in addition to the number of nucleosomes bound and the degree of protein-DNA interaction, previously reported (Martino and Olson, 1997). Small changes in spacing can support dramatic configurational transitions and are biologically relevant in that they determine DNA compaction and sites of inter-and intra-linker approach.…”

“…The Cartesian coordinates of the starting state are constructed in a piecewise manner following methodology detailed elsewhere (Martino and Olson, 1997). Briefly, pitched circular arcs and helices are generated using standard equations and spliced together using Mathematica.…”

“…Minichromosomes of different chain lengths provide excellent models for the next level of DNA structural organization in eukaryotes above the (tertiary) nucleosomal wrapping of the double helix: topologically autonomous chromatin domains (Paulson and Laemmli, 1977;Marsden and Laemmli, 1979). Recent efforts to model chain folding in minichromosomes using B-spline curves have demonstrated that the number of nucleosome complexes bound by the chain and the degree of protein-DNA interaction within each complex are important determinants of the extent of chain folding (Martino and Olson, 1997). One specific outcome is a novel resolution to the discrepancy between measured and modeled changes in linking number upon nucleosome formation.…”

Looping Dynamics of Linear DNA Molecules and the Effect of DNA Curvature: A Study by Brownian Dynamics Simulation

“…Such a model may be used to calculate thermodynamic equilibrium structural ensembles through Monte Carlo procedures (Bednar et al, 1994;Gebe et al, 1995;Gebe and Schurr, 1996;Klenin et al, 1995Klenin et al, , 1991Kremer et al, 1993;Rybenkov et al, 1997a,b;Vologodskii et al, 1992) and also to describe the dynamics of DNA on microto-millisecond time scales by Brownian dynamics (BD) procedures (Allison et al, 1989(Allison et al, , 1990Chirico and Langowski, 1992, 1996Ehrlich et al, 1997;Heath et al, 1996). Other types of models, notably elastic-chain models using finite-element or spline function approaches (Martino and Olson, 1997;Olson, 1996;Olson et al, 1993;Schlick and Olson, 1992;Yang et al, 1995;Zhang et al, 1994) have been used to calculate structural properties of large DNAs, but these models, which exclude thermal fluctuations, are not adequate for computing thermodynamic properties (Langowski et al, 1996).…”