Student: David McCandlish, Swarthmore College
Mentor: Wilma
Olson, Department of Chemistry, Rutgers University
Introduction:
The primary structural unit of eukaryotic chromosomal DNA is the nucleosome. Each nucleosome consists of 146 DNA basepairs wrapped 1.65 times around a core protein called a histone. Eukaryotic chromosomal DNA is generally packaged as a long series of nucleosomes joined by shorter DNA segments. This packing scheme helps to fit the DNA within the cell nucleus.
It turns out that some DNA sequences have a greater affinity
to bond to the histone protein than others. This has particular biological
significance because the DNA must be unwound from the histone prior
to being transcribed. Thus a particular sequence binding strongly to a
histone may result in decreased gene expression in the gene containing
that sequence. Our hypothesis is that the local DNA structure implied by
a particular base sequence may result in a greater or lesser affinity for
the histone protein.
Project Description:
By Euler's Rotation Theorem, it takes 6 parameters, 3 translations and 3 rotations to uniquely describe the spatial relationship between the ith and i+1th basepairs. These six parameters are called the step parameters. From experimental data, it appears that 3 of the step parameters have a dominant effect on the structure (the other 3 are largely constrained by the limited flexibility of the sugar-phosphate backbone and the steric interactions between adjacent basepairs). My first task is to write a perl program to take experimentally derived step parameters, replace the 3 less important step parameters with constants, calculate the new structure implied by these parameters and do an RMS fit with the original structure to determine the error induced by this approximation.
The next part of my project is to write a program to use known average step parameters from a given basepair to the next to simulate wrapping an arbitrary sequence of basepairs around a histone. Hopefully, the results of experimenting with my first program will allow me to write this second program using only 3 variable step parameters. Finally, I will use this second program to calculate simulated structures for biologically significant sequences known to have greater and lesser affinity for the nucleosome. By comparing and contrasting these simulated structures I hope to be able to gain some insight into the relationship between DNA sequence and histone affinity.