Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Nucleosomal Minor Groove Shape and Electrostatics Provide a Molecular Origin for Histone Arginine Binding
We recently established local shape recognition as a new protein-DNA readout mechanism and identified the readout of minor groove shape as the molecular origin of Hox specificity [1, 2]. A bioinformatics analysis of all protein-DNA complexes in the PDB with arginine contacts in narrow minor groove regions indicates that this new readout mechanism is of a general nature. Narrow minor groove geometry induces enhanced negative electrostatic potentials as a result of electrostatic ?focusing?, which describes the enhanced magnitude of electric fields in narrow pockets on the surface of macromolecules . In the case of the DNA minor groove, field lines that originate from the bases and lead into the solvent are compressed by the electrostatic boundary of the minor groove walls. Differences in electrostatic minor groove potential of AT vs. GC-rich sequences have been noted earlier but the impact of the electrostatic ?focusing? effect is approximately an order of magnitude larger. The architecture of the nucleosome exhibits elements of the local shape recognition mechanism. Nucleosomal DNA is highly deformed when wrapped around histones. Due to histone binding, narrow minor groove regions in the nucleosome are equally spaced by a helical turn with minor groove width fluctuating between approximately 3 and 8 Å. Electrostatic potential strongly correlates with minor groove geometry ranging from -2 to -12 kT/e.
Enhanced negative electrostatic potential attracts basic side chains into the minor groove and is a biophysical reason for the dominance of arginine among minor groove binding residues. For the only nucleosome structure that includes histone tails, 1kx5 , arginine residues are frequently found to take advantage of enhanced negative electrostatic potential in narrow minor groove regions. Many of the histone binding sites contain short A-tracts or A-tract-like trimers in their narrow minor groove region. A narrow minor groove is a common sequence-dependent feature of A-tracts [4, 5], which explains the correlation of these short A-tract sequences with arginine binding sites. Monte Carlo simulations of unbound DNA confirm the sequence-dependent tendendency of A-tract minor grooves to be narrow . Intrinsically pre-formed regions modulate deformations required for histone binding, release strain, and, importantly, attract arginines through electrostatic means and stabilize the nucleosome complex. Since arginine attraction in A-tract regions is associated with local shape readout, arginine-minor groove recognition can be expected to play a role in nucleosome positioning.
References and Footnotes