Protein Structure Validation and Refinement Using Amide Proton Chemical Shifts Derived from Quantum Mechanics |
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| Authors: | Anders S. Christensen Troels E. Linnet Mikael Borg Wouter Boomsma Kresten Lindorff-Larsen Thomas Hamelryck Jan H. Jensen |
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| Affiliation: | 1. Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.; 2. Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.; 3. Structural Bioinformatics Group, Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.; Wake Forest University, United States of America, |
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| 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 (h3JNC'') 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. |
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