title: Prediction of (19)F NMR Chemical Shifts in Labeled Proteins: Computational Protocol and Case Study.
abstract: The structural analysis of ligand complexation in biomolecular systems is important in the design of new medicinal therapeutic agents; however, monitoring subtle structural changes in a protein's microenvironment is a challenging and complex problem. In this regard, the use of protein-based (19)F NMR for screening low-molecular-weight molecules (i.e., fragments) can be an especially powerful tool to aid in drug design. Resonance assignment of the protein's (19)F NMR spectrum is necessary for structural analysis. Here, a quantum chemical method has been developed as an initial approach to facilitate the assignment of a fluorinated protein's (19)F NMR spectrum. The epigenetic "reader" domain of protein Brd4 was taken as a case study to assess the strengths and limitations of the method. The overall modeling protocol predicts chemical shifts for residues in rigid proteins with good accuracy; proper accounting for explicit solvation of fluorinated residues by water is critical.
authors.affiliation: Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Isley
authors.affiliation: Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Urick
authors.affiliation: Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: William C K
authors.initials: WC
authors.lastname: Pomerantz
authors.affiliation: Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cramer
mesh_terms: D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012984:Software; D014157:Transcription Factors / Q000737:chemistry; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D011506:Proteins; D014157:Transcription Factors; C001245:3-fluorotyrosine; D014443:Tyrosine
keywords: 19F NMR; DFT; NMR; bromodomain; fluorine; screening