title: Proliferating cell nuclear antigen loaded onto double-stranded DNA: dynamics, minor groove interactions and functional implications.
abstract: Proliferating cell nuclear antigen (PCNA) acts as a biologically essential processivity factor that encircles DNA and provides binding sites for polymerase, flap endonuclease-1 (FEN-1) and ligase during DNA replication and repair. We have computationally characterized the interactions of human and Archaeoglobus fulgidus PCNA trimer with double-stranded DNA (ds DNA) using multi-nanosecond classical molecular dynamics simulations. The results reveal the interactions of DNA passing through the PCNA trimeric ring including the contacts formed, overall orientation and motion with respect to the sliding clamp. Notably, we observe pronounced tilting of the axis of dsDNA with respect to the PCNA ring plane reflecting interactions between the DNA phosphodiester backbone and positively charged arginine and lysine residues lining the PCNA inner surface. Covariance matrix analysis revealed a pattern of correlated motions within and between the three equivalent subunits involving the PCNA C-terminal region and linker strand associated with partner protein binding sites. Additionally, principal component analysis identified low frequency global PCNA subunit motions suitable for translocation along duplex DNA. The PCNA motions and interactions with the DNA minor groove, identified here computationally, provide an unexpected basis for PCNA to act in the coordinated handoff of intermediates from polymerase to FEN-1 to ligase during DNA replication and repair.
authors.affiliation: Department of Chemistry and Biochemistry, Howard Hughes Medical Institute and Center for Theoretical Biological Physics, University of California-San Diego, 9500 Gilman Drive La Jolla, CA 92093-0365, USA. iivanov@mccammon.ucsd.edu
authors.forename: Ivaylo
authors.initials: I
authors.lastname: Ivanov
authors.forename: Brian R
authors.initials: BR
authors.lastname: Chapados
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D009038:Motion; D009690:Nucleic Acid Conformation; D025341:Principal Component Analysis; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D021122:Protein Subunits; D004247:DNA