It has been shown previously that local DNA flexibility depends on the sequence of nucleic acids.  We have considered the DNA as a flexible hetero-polymer composed of units of base-pair steps in order to develop an understanding of local DNA dynamics.  This approach treats each base pair in a base-pair step as a rigid body.  Thus, the vibrational properties at the local level can be characterized by three translations (shift, slide, and rise) and three rotations (tilt, roll, and twist).  To obtain an extensive sampling of DNA vibrations we have conducted 5 ns MD simulations of several DNA 11-mers of differing sequence in a periodic box with explicit water and counter ions.  The AMBER force field was used and long-range electrostatic interactions were calculated with Ewald sums.  The trajectories were used to analyze the local vibrational properties of the ten unique base-pair step combinations with two methods.  In the first method, quasi-harmonic analysis is used to determine the quasi-normal modes for each base-pair step.  The trace of the covariance matrix yields a measure of the total local flexibility for each base pair step.  The eigenvalues and the eigenvectors from the quasiharmonic analysis are related to the force constants and the direction of motion within a given quasi-normal mode.  However, inspection of the quasi-normal modes shows that they do not represent simple translations or rotations, but rather are linear combinations of such motions.  Thus, the force constants derived from this analysis are not easily translated into a usable ?force field?.  In the second approach, a potential of mean force (PMF) is derived for each motion within the base-pair step.  By assuming that the motions are uncoupled, we calculate individual force constants for each of the six motions, which are easily translated into a force field.  The PMF analysis was performed with respect to a globalhelical axis, and with respect to a local helical axis.
 In the local context, the TA step is the most flexible, in agreement with previously determined local base pair step flexibility.  However, in clear distinction from previous results the AC step is observed to be the most rigid. The analysis with respect to a global helical axis generates a different rank order of flexibilities, illustrating the effect of the neighboring bases on the dynamical properties of the base-pair step.  The force constants derived from this approach will be used to develop an approximate force field.  Such a force field, in which the DNA is represented as rigid bodies, will reduce the computational expense for simulations of long DNA sequences on realistic time scales.
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<B>Supported by PHS Grant CA 63317<B>