Mapping the structural and dynamical features of multiple p53 DNA binding domains: insights into loop 1 intrinsic dynamics

• Published in: PloS one Vol. 8; no. 11; p. e80221
• Main Authors: Lukman, Suryani, Lane, David P, Verma, Chandra S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.11.2013; Public Library of Science (PLoS)
• Subjects: Algorithms; Amino Acid Sequence; Binding; Bioinformatics; Biopolymers; Deoxyribonucleic acid; DNA; DNA binding; Magnetic Resonance Spectroscopy; Molecular dynamics; Molecular Dynamics Simulation; Molecular Sequence Data; Mutation; p53 Protein; Principal Component Analysis; Principal components analysis; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Science; Simulation; Solvents; Transcription (Genetics); Tumor proteins; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism; Variation; Singapore
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0080221

The transcription factor p53 regulates cellular integrity in response to stress. p53 is mutated in more than half of cancerous cells, with a majority of the mutations localized to the DNA binding domain (DBD). In order to map the structural and dynamical features of the DBD, we carried out multiple copy molecular dynamics simulations (totaling 0.8 μs). Simulations show the loop 1 to be the most dynamic element among the DNA-contacting loops (loops 1-3). Loop 1 occupies two major conformational states: extended and recessed; the former but not the latter displays correlations in atomic fluctuations with those of loop 2 (~24 Å apart). Since loop 1 binds to the major groove whereas loop 2 binds to the minor groove of DNA, our results begin to provide some insight into the possible mechanism underpinning the cooperative nature of DBD binding to DNA. We propose (1) a novel mechanism underlying the dynamics of loop 1 and the possible tread-milling of p53 on DNA and (2) possible mutations on loop 1 residues to restore the transcriptional activity of an oncogenic mutation at a distant site.