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

ABSTRACT: A server (CheShift) has been developed to predict (13)C(alpha) chemical shifts of protein structures. It is based on the generation of 696,916 conformations as a function of the phi, psi, omega, chi1 and chi2 torsional angles for all 20 naturally occurring amino acids. Their (13)C(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 (13)C(alpha) chemical shifts, was carried out for 3 sets of conformations: (i) 36 x-ray-derived protein structures solved at 2.3 A or better resolution, for which sets of (13)C(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 A. 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 (13)C(alpha) chemical shifts are available. CheShift is available as a web server.

SUBMITTER: Vila JA

PROVIDER: S-EPMC2761357 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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

Vila Jorge A JA Arnautova Yelena A YA Martin Osvaldo A OA Scheraga Harold A HA

Proceedings of the National Academy of Sciences of the United States of America 20090908 40

A server (CheShift) has been developed to predict (13)C(alpha) chemical shifts of protein structures. It is based on the generation of 696,916 conformations as a function of the phi, psi, omega, chi1 and chi2 torsional angles for all 20 naturally occurring amino acids. Their (13)C(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 se ...[more]

PMID: 19805131

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Project description:The accurate prediction of protein chemical shifts using a quantum mechanics (QM)-based method has been the subject of intense research for more than 20 years but so far empirical methods for chemical shift prediction have proven more accurate. In this paper we show that a QM-based predictor of a protein backbone and CB chemical shifts (ProCS15, PeerJ, 2016, 3, e1344) is of comparable accuracy to empirical chemical shift predictors after chemical shift-based structural refinement that removes small structural errors. We present a method by which quantum chemistry based predictions of isotropic chemical shielding values (ProCS15) can be used to refine protein structures using Markov Chain Monte Carlo (MCMC) simulations, relating the chemical shielding values to the experimental chemical shifts probabilistically. Two kinds of MCMC structural refinement simulations were performed using force field geometry optimized X-ray structures as starting points: simulated annealing of the starting structure and constant temperature MCMC simulation followed by simulated annealing of a representative ensemble structure. Annealing of the CHARMM structure changes the CA-RMSD by an average of 0.4 Å but lowers the chemical shift RMSD by 1.0 and 0.7 ppm for CA and N. Conformational averaging has a relatively small effect (0.1-0.2 ppm) on the overall agreement with carbon chemical shifts but lowers the error for nitrogen chemical shifts by 0.4 ppm. If an amino acid specific offset is included the ProCS15 predicted chemical shifts have RMSD values relative to experiments that are comparable to popular empirical chemical shift predictors. The annealed representative ensemble structures differ in CA-RMSD relative to the initial structures by an average of 2.0 Å, with >2.0 Å difference for six proteins. In four of the cases, the largest structural differences arise in structurally flexible regions of the protein as determined by NMR, and in the remaining two cases, the large structural change may be due to force field deficiencies. The overall accuracy of the empirical methods are slightly improved by annealing the CHARMM structure with ProCS15, which may suggest that the minor structural changes introduced by ProCS15-based annealing improves the accuracy of the protein structures. Having established that QM-based chemical shift prediction can deliver the same accuracy as empirical shift predictors we hope this can help increase the accuracy of related approaches such as QM/MM or linear scaling approaches or interpreting protein structural dynamics from QM-derived chemical shift.

Project description:In quantum mechanics, the theory of quantum transitions is grounded on the convergence of a series of time-dependent perturbation theory. In nuclear and atomic physics, this series converges because the dynamics of quantum transitions (quantum jumps) are absent by definition. In molecular and chemical physics, on the contrary, the dynamics of "quantum" transitions, being determined by the joint motion of a light electron (or electrons) and very heavy nuclei, are present by definition, and the series of time-dependent perturbation theory becomes singular. An exception is the dynamic problem for stationary states in the Born-Oppenheimer adiabatic approximation, when the electronic subsystem turns out to be "off" from the general dynamic process and therefore is not dynamically full-fledged: it only forms an electric potential in which the nuclei oscillate. Removing the aforementioned singularity can be accomplished in two ways. The first method was consisted of introducing an additional postulate in the form of the Franck-Condon principle into molecular quantum mechanics, in which the adiabatic approximation is used. The second method was proposed by the author and consisted of damping the singular dynamics of the joint motion of an electron and nuclei in the intermediate (transient) state of molecular "quantum" transitions by introducing chaos. This chaos arises only during molecular quantum transitions and is called dozy chaos. Formally, the damping is carried out by replacing an infinitely small imaginary addition in the spectral representation of the complete Green's function of the system with its finite quantity. The damping chaos (dozy chaos) leads to the continuity of the energy spectrum in the molecular transient state, which is a sign of classical mechanics. Meanwhile, the initial and final states of the molecule obey quantum mechanics in the adiabatic approximation. Molecular quantum mechanics, which takes into account the chaotic dynamics of the transient state of molecular "quantum" transitions, can be called quantum-classical (dozy-chaos) mechanics. The efficacy of the damping for the aforementioned singularity was previously shown by dozy-chaos mechanics of elementary electron transfers in condensed matter, which is the simplest case of dozy-chaos mechanics, and its applications to a whole number of problems, especially to the optical spectra in polymethine dyes and their aggregates. This paper provides a regular exposition of this dozy-chaos (quantum-classical) mechanics of the elementary electron transfers. The main results of its applications presented in the introduction are also described.

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

Publications

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

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