Prediction of (19)F NMR Chemical Shifts in Labeled Proteins: Computational Protocol and Case Study.

Autor:	Isley WC 3rd; Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Urick AK; Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Pomerantz WC; Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Cramer CJ; Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
Jazyk:	angličtina
Zdroj:	Molecular pharmaceutics [Mol Pharm] 2016 Jul 05; Vol. 13 (7), pp. 2376-86. Date of Electronic Publication: 2016 Jun 02.
DOI:	10.1021/acs.molpharmaceut.6b00137
Abstrakt:	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.
Databáze:	MEDLINE
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