Quantum-mechanics-derived 13Cα chemical shift server (CheShift) for protein structure validation

A server (CheShift) has been developed to predict C-13(alpha) chemical shifts of protein structures. It is based on the generation of 696,916 conformations as a function of the phi, psi, omega, chi 1 and chi 2 torsional angles for all 20 naturally occurring amino acids. Their C-13(alpha) chemical shifts were computed at the DFT level of theory with a small basis set and extrapolated, with an empirically-determined linear regression formula, to reproduce the values obtained with a larger basis set. Analysis of the accuracy and sensitivity of the CheShift predictions, in terms of both the correlation coefficient R and the conformational-averaged rmsd between the observed and predicted C-13(alpha) chemical shifts, was carried out for 3 sets of conformations: (i) 36 x-ray-derived protein structures solved at 2.3 angstrom or better resolution, for which sets of C-13(alpha) chemical shifts were available; (ii) 15 pairs of x-ray and NMR-derived sets of protein conformations; and (iii) a set of decoys for 3 proteins showing an rmsd with respect to the x-ray structure from which they were derived of up to 3 angstrom. Comparative analysis carried out with 4 popular servers, namely SHIFTS, SHIFTX, SPARTA, and PROSHIFT, for these 3 sets of conformations demonstrated that CheShift is the most sensitive server with which to detect subtle differences between protein models and, hence, to validate protein structures determined by either x-ray or NMR methods, if the observed C-13(alpha) chemical shifts are available. CheShift is available as a web server.