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Use of 13Calpha chemical shifts in protein structure determination.

ABSTRACT: A physics-based method aimed at determining protein structures by using NOE-derived distances together with observed and computed 13C chemical shifts is proposed. The approach makes use of 13Calpha chemical shifts, computed at the density functional level of theory, to obtain torsional constraints for all backbone and side-chain torsional angles without making a priori use of the occupancy of any region of the Ramachandran map by the amino acid residues. The torsional constraints are not fixed but are changed dynamically in each step of the procedure, following an iterative self-consistent approach intended to identify a set of conformations for which the computed 13Calpha chemical shifts match the experimental ones. A test is carried out on a 76-amino acid, all-alpha-helical protein; namely, the Bacillus subtilis acyl carrier protein. It is shown that, starting from randomly generated conformations, the final protein models are more accurate than an existing NMR-derived structure model of this protein, in terms of both the agreement between predicted and observed 13Calpha chemical shifts and some stereochemical quality indicators, and of similar accuracy as one of the protein models solved at a high level of resolution. The results provide evidence that this methodology can be used not only for structure determination but also for additional protein structure refinement of NMR-derived models deposited in the Protein Data Bank.

SUBMITTER: Vila JA

PROVIDER: S-EPMC2597024 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Use of 13Calpha chemical shifts in protein structure determination.

Vila Jorge A JA Ripoll Daniel R DR Scheraga Harold A HA

The journal of physical chemistry. B 20070522 23

A physics-based method aimed at determining protein structures by using NOE-derived distances together with observed and computed 13C chemical shifts is proposed. The approach makes use of 13Calpha chemical shifts, computed at the density functional level of theory, to obtain torsional constraints for all backbone and side-chain torsional angles without making a priori use of the occupancy of any region of the Ramachandran map by the amino acid residues. The torsional constraints are not fixed b ...[more]

PMID: 17516673

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Project description:The room-temperature X-ray structures of ubiquitin (PDB code 1ubq) and of the RNA-binding domain of nonstructural protein 1 of influenza A virus (PDB code 1ail) solved at 1.8 and 1.9 A resolution, respectively, were used to investigate whether a set of conformations rather than a single X-ray structure provides better agreement with both the X-ray data and the observed 13Calpha chemical shifts in solution. For this purpose, a set of new conformations for each of these proteins was generated by fitting them to the experimental X-ray data deposited in the PDB. For each of the generated structures, which show R and Rfree factors similar to those of the deposited X-ray structure, the 13Calpha chemical shifts of all residues in the sequence were computed at the DFT level of theory. The sets of conformations were then evaluated by their ability to reproduce the observed 13Calpha chemical shifts by using the conformational average root-mean-square-deviation (ca-r.m.s.d.). For ubiquitin, the computed set of conformations is a better representation of the observed 13Calpha chemical shifts in terms of the ca-r.m.s.d. than a single X-ray-derived structure. However, for the RNA-binding domain of nonstructural protein 1 of influenza A virus, consideration of an ensemble of conformations does not improve the agreement with the observed 13Calpha chemical shifts. Whether an ensemble of conformations rather than any single structure is a more accurate representation of a protein structure in the crystal as well as of the observed 13Calpha chemical shifts is determined by the dispersion of coordinates, in terms of the all-atom r.m.s.d. among the generated models; these generated models satisfy the experimental X-ray data with accuracy as good as the PDB structure. Therefore, generation of an ensemble is a necessary step to determine whether or not a single structure is sufficient for an accurate representation of both experimental X-ray data and observed 13Calpha chemical shifts in solution.

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Use of 13Calpha chemical shifts in protein structure determination.

Publications

Use of 13Calpha chemical shifts in protein structure determination.

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