title: Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics.
abstract: We present the ProCS method for the rapid and accurate prediction of protein backbone amide proton chemical shifts--sensitive probes of the geometry of key hydrogen bonds that determine protein structure. ProCS is parameterized against quantum mechanical (QM) calculations and reproduces high level QM results obtained for a small protein with an RMSD of 0.25 ppm (r = 0.94). ProCS is interfaced with the PHAISTOS protein simulation program and is used to infer statistical protein ensembles that reflect experimentally measured amide proton chemical shift values. Such chemical shift-based structural refinements, starting from high-resolution X-ray structures of Protein G, ubiquitin, and SMN Tudor Domain, result in average chemical shifts, hydrogen bond geometries, and trans-hydrogen bond ((h3)J(NC')) spin-spin coupling constants that are in excellent agreement with experiment. We show that the structural sensitivity of the QM-based amide proton chemical shift predictions is needed to obtain this agreement. The ProCS method thus offers a powerful new tool for refining the structures of hydrogen bonding networks to high accuracy with many potential applications such as protein flexibility in ligand binding.
authors.affiliation: Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders S
authors.initials: AS
authors.lastname: Christensen
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Troels E
authors.initials: TE
authors.lastname: Linnet
authors.affiliation: Structural Bioinformatics Group, Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mikael
authors.initials: M
authors.lastname: Borg
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Wouter
authors.initials: W
authors.lastname: Boomsma
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.affiliation: Structural Bioinformatics Group, Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hamelryck
authors.affiliation: Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Jensen
mesh_terms: D000577:Amides / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011522:Protons; D011789:Quantum Theory; D055532:SMN Complex Proteins / Q000737:chemistry*; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D000577:Amides; D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus; D011522:Protons; D055532:SMN Complex Proteins; D025801:Ubiquitin