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Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation.

ABSTRACT: A recently determined set of 20 NMR-derived conformations of a 48-residue all-alpha-helical protein, (PDB ID code 2JVD), is validated here by comparing the observed (13)C(alpha) chemical shifts with those computed at the density functional level of theory. In addition, a recently introduced physics-based method, aimed at determining protein structures by using NOE-derived distance constraints together with observed and computed (13)C(alpha) chemical shifts, was applied to determine a new set of 10 conformations, (Set-bt), as a blind test for the same protein. A cross-validation of these two sets of conformations in terms of the agreement between computed and observed (13)C(alpha) chemical shifts, several stereochemical quality factors, and some NMR quality assessment scores reveals the good quality of both sets of structures. We also carried out an analysis of the agreement between the observed and computed (13)C(alpha) chemical shifts for a slightly longer construct of the protein solved by x-ray crystallography at 2.0-A resolution (PDB ID code 3BHP) with an identical amino acid residue sequence to the 2JVD structure for the first 46 residues. Our results reveal that both of the NMR-derived sets, namely 2JVD and Set-bt, are somewhat better representations of the observed (13)C(alpha) chemical shifts in solution than the 3BHP crystal structure. In addition, the (13)C(alpha)-based validation analysis appears to be more sensitive to subtle structural differences across the three sets of structures than any other NMR quality-assessment scores used here, and, although it is computationally intensive, this analysis has potential value as a standard procedure to determine, refine, and validate protein structures.

SUBMITTER: Vila JA

PROVIDER: S-EPMC2567219 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation.

Vila Jorge A JA Aramini James M JM Rossi Paolo P Kuzin Alexandre A Su Min M Seetharaman Jayaraman J Xiao Rong R Tong Liang L Montelione Gaetano T GT Scheraga Harold A HA

Proceedings of the National Academy of Sciences of the United States of America 20080911 38

A recently determined set of 20 NMR-derived conformations of a 48-residue all-alpha-helical protein, (PDB ID code 2JVD), is validated here by comparing the observed (13)C(alpha) chemical shifts with those computed at the density functional level of theory. In addition, a recently introduced physics-based method, aimed at determining protein structures by using NOE-derived distance constraints together with observed and computed (13)C(alpha) chemical shifts, was applied to determine a new set of ...[more]

PMID: 18787110

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Project description:When using nuclear magnetic resonance (NMR) to assist in chemical identification in complex samples, researchers commonly rely on databases for chemical shift spectra. However, authentic standards are typically depended upon to build libraries experimentally. Considering complex biological samples, such as blood and soil, the entirety of NMR spectra required for all possible compounds would be infeasible to ascertain due to limitations of available standards and experimental processing time. As an alternative, we introduce the in silico Chemical Library Engine (ISiCLE) NMR chemical shift module to accurately and automatically calculate NMR chemical shifts of small organic molecules through use of quantum chemical calculations. ISiCLE performs density functional theory (DFT)-based calculations for predicting chemical properties-specifically NMR chemical shifts in this manuscript-via the open source, high-performance computational chemistry software, NWChem. ISiCLE calculates the NMR chemical shifts of sets of molecules using any available combination of DFT method, solvent, and NMR-active nuclei, using both user-selected reference compounds and/or linear regression methods. Calculated NMR chemical shifts are provided to the user for each molecule, along with comparisons with respect to a number of metrics commonly used in the literature. Here, we demonstrate ISiCLE using a set of 312 molecules, ranging in size up to 90 carbon atoms. For each, calculation of NMR chemical shifts have been performed with 8 different levels of DFT theory, and with solvation effects using the implicit solvent Conductor-like Screening Model. The DFT method dependence of the calculated chemical shifts have been systematically investigated through benchmarking and subsequently compared to experimental data available in the literature. Furthermore, ISiCLE has been applied to a set of 80 methylcyclohexane conformers, combined via Boltzmann weighting and compared to experimental values. We demonstrate that our protocol shows promise in the automation of chemical shift calculations and, ultimately, the expansion of chemical shift libraries.

Dataset Information

Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation.

Publications

Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation.

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