Performance of Density Functional Models to Reproduce Observed 13Cα Chemical Shifts of Proteins in Solution

The purpose of this work is to test several density functional models (namely, OPBE, O3LYP, OPW91, BPW91, OB98, BPBE, B971, OLYP, PBE1PBE, and B3LYP) to determine their accuracy and speed for computing C-13(alpha) chemical shifts in proteins. The test is applied to 10 NMR-derived conformations of the 76-residue alpha/beta protein ubiquitin (protein data bank id 1D3Z). With each functional, the C-13(alpha) shielding was computed for 760 amino acid residues by using a combination of approaches that includes, but is not limited to, treating each amino acid X in the sequence as a terminally blocked tripeptide with the sequence Ac-GXG-NMe in the conformation of the regularized experimental protein structure. As computation of the C-13(alpha) chemical shifts, not their shielding, is the main goal of this work, a computation of the C-13(alpha) shielding of the reference, namely, tetramethylsilane, is investigated here and an effective and a computed tetramethylsilane shielding value for each of the functionals is provided. Despite observed small differences among all functionals tested, the results indicate that four of them, namely, OPBE, OPW91, OB98, and OLYP, provide the most accurate functionals with which to reproduce observed C-13(alpha) chemical shifts of proteins in solution, and are among the faster ones. This study also provides evidence for the applicability of these functionals to proteins of any size or class, and for the validation of our previous results and conclusions, obtained from calculations with the slower 133LYP functional. (C) 2008 Wiley Periodicals, Inc. J Comput Chem 30: 884-892, 2009