Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics

TY - JOUR

T1 - Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics

AU - Christensen, Anders Steen

AU - Linnet, Troels Emtekær

AU - Borg, Mikael

AU - Boomsma, Wouter Krogh

AU - Lindorff-Larsen, Kresten

AU - Hamelryck, Thomas Wim

AU - Jensen, Jan Halborg

N1 - O.A.

PY - 2013/12/31

Y1 - 2013/12/31

N2 - 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) JNC' ) 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.

AB - 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) JNC' ) 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.

U2 - 10.1371/journal.pone.0084123

DO - 10.1371/journal.pone.0084123

M3 - Journal article

C2 - 24391900

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 12

M1 - e84123

ER -