title: Investigation of arc repressor DNA-binding specificity by comparative molecular dynamics simulations.
abstract: Transcription factors regulate gene expression through binding to specific DNA sequences. How transcription factors achieve high binding specificity is still not well understood. In this paper, we investigated the role of protein flexibility in protein-DNA-binding specificity by comparative molecular dynamics (MD) simulations. Protein flexibility has been considered as a key factor in molecular recognition, which is intrinsically a dynamic process involving fine structural fitting between binding components. In this study, we performed comparative MD simulations on wild-type and F10V mutant P22 Arc repressor in both free and complex conformations. The F10V mutant has lower DNA-binding specificity though both the bound and unbound main-chain structures between the wild-type and F10V mutant Arc are highly similar. We found that the DNA-binding motif of wild-type Arc is structurally more flexible than the F10V mutant in the unbound state, especially for the six DNA base-contacting residues in each dimer. We demonstrated that the flexible side chains of wild-type Arc lead to a higher DNA-binding specificity through forming more hydrogen bonds with DNA bases upon binding. Our simulations also showed a possible conformational selection mechanism for Arc-DNA binding. These results indicate the important roles of protein flexibility and dynamic properties in protein-DNA-binding specificity.
authors.affiliation: a Department of Bioinformatics and Genomics , University of North Carolina at Charlotte , Charlotte , NC 28223 , USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Jun-Tao
authors.initials: JT
authors.lastname: Guo
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D017100:Bacteriophage P22 / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D004279:DNA, Viral / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D010649:Phenylalanine / Q000737:chemistry*; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics; D013816:Thermodynamics; D014633:Valine / Q000737:chemistry*; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D004279:DNA, Viral; D012097:Repressor Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; D010649:Phenylalanine; D014633:Valine
keywords: arc repressor; binding specificity; molecular dynamics simulations; protein flexibility; transcription factor