Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Sequence Dependence of DNA Bending upon p53 Binding: A Molecular Dynamics Simulation

Specific p53-binding induced DNA bending has important biological implications such as transcription activation. However, the detailed structures of the bent DNA and the p53-DNA complex are still unavailable, hampering our understanding of the mechanism for p53-induced DNA bending and its consequent biological significance. We constructed p53-DNA complex models with one, two, and four p53 core domains in bound and performed molecular dynamics simulations. We show that each DNA-bound p53 core domain caused a local DNA conformational change within the quarter site. Upon the binding of the p53 dimer, there is an apparent DNA bending at the center of the half site. When bound with two p53 dimers, the DNA bent about 20 and 35 degrees for two different DNA sequences, respectively, which is in agreement with experimental observations. The results suggest that the two p53 dimers favored a staggered conformation in which they complemented and interacted with each other to stabilize the complex. This dimer-dimer interface organization necessitated conformational changes in the DNA, leading to the enhanced bending at the centers of the half sites and to the conformational change at the middle of the full site.

We further performed MD simulations to test the sequence dependence of DNA bending. We particularly focused on the DNA bending properties of the complexes with DNA sequences of CATG, CAAG, CTTG, and CTAG at the centers of the two DNA half sites. We show that the DNA bending extent is dependent on the DNA sequence, with CATG the most flexible and bendable and CAAG, CTTG, CTAG in decreasing order of bending extent.

Overall, we show that the two p53 dimers in bound with consensus DNA site favored a staggered conformation in which they make favorable interactions at the interface. The more flexible DNA allowed the two dimers to approach to each closer while the less flexible DNA hampered the interactions between the dimers. Our results provide the detailed atomic model for the DNA-p53 tetramer complex and delineate the roles of DNA-p53 and p53 dimer-dimer interactions in specific DNA-p53 binding induced DNA conformational change.

Yongping Pan1,*
Ruth Nussinov1, 2

1Center for Cancer Research Nanobiology Program
SAIC-Frederick, Inc.
Frederick, MD 21702
2Sackler Inst. of Molecular Medicine
Department of Human Molecular Genetics and Biochemistry
NCI-Frederick Bldg 469
Rm 151
Frederick, MD 21702

*Phone: 301-846-1424
Fax: 301-846-5598
Email: pany@ncifcrf.gov