title: Does bromodomain flexibility influence histone recognition?
abstract: Bromodomains are protein modules that selectively recognize histones by binding to acetylated lysines. Here, we have carried out multiple molecular dynamics simulations of 20 human bromodomains to investigate the flexibility of their binding site. Some bromodomains show alternative side chain orientations of three evolutionarily conserved residues: the Asn involved in acetyl-lysine binding and two conserved aromatic residues. Furthermore, for the BAZ2B and CREBBP bromodomains we observe occlusion of the binding site which is coupled to the displacement of the two aromatic residues. In contrast to available structures, the simulations reveal large variability of the binding site accessibility. The simulations suggest that the flexibility of the bromodomain binding site and presence of self-occluded metastable states influence the recognition of acetyl-lysine on histone tails.
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Steiner
authors.forename: Andrea
authors.initials: A
authors.lastname: Magno
authors.forename: Danzhi
authors.initials: D
authors.lastname: Huang
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000737:chemistry; D020816:Amino Acid Motifs; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000737:chemistry; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry; D004265:DNA Helicases / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D051548:Histone Acetyltransferases / Q000737:chemistry; D056488:Histone Chaperones; D006657:Histones / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000737:chemistry; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D035381:TATA-Binding Protein Associated Factors / Q000737:chemistry; D035362:Transcription Factor TFIID / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry; D000092468:Bromodomain Containing Proteins
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases; D050882:CREB-Binding Protein; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006657:Histones; D009687:Nuclear Proteins; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C109570:BRDT protein, human; D000092468:Bromodomain Containing Proteins; C402649:BRD1 protein, human; C494363:CREBBP protein, human; C069001:TATA-binding protein associated factor 250 kDa; C084108:SMARCA4 protein, human; C544857:ATAD2 protein, human; C558789:ATAD2B protein, human