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University of Groningen NMR Chemical Shift Data and Ab Initio University of Groningen NMR chemical shift data and ab initio shielding calculations Mulder, Frans A. A.; Filatov, Michael Published in: Chemical Society Reviews DOI: 10.1039/b811366c IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2010 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Mulder, F. A. A., & Filatov, M. (2010). NMR chemical shift data and ab initio shielding calculations: emerging tools for protein structure determination. Chemical Society Reviews, 39(2), 578-590. https://doi.org/10.1039/b811366c Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 12-11-2019 TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews NMR chemical shift data and ab initio shielding calculations: emerging tools for protein structure determination Frans A. A. Muldera and Michael Filatovb Received 29th June 2009 First published as an Advance Article on the web 4th November 2009 DOI: 10.1039/b811366c In this tutorial review, we discuss the utilization of chemical shift information as well as ab initio calculations of nuclear shieldings for protein structure determination. Both the empirical and computational aspects of the chemical shift are reviewed and the role of molecular dynamics and the accuracy of different computational methods are discussed. It is anticipated that incorporating theoretical information on chemical shifts will increase the accuracy of protein structures, in the solid and liquid state alike, and extend the applicability of NMR spectroscopy to ever larger systems. I. Introduction natural milieu. The continued success of NMR spectroscopy is largely due to the constant development of NMR spectroscopy Over the past decades nuclear magnetic resonance (NMR) as a technique. Important advances include improvements spectroscopy has established itself as a powerful technique to in instrumentation hardware, pulse sequence development, determine the three-dimensional (3D) structures of biological access to residual anisotropic interactions, (bio)synthetic macromolecules at atomic resolution, and a valuable comple- isotope enrichment schemes, and in vivo, in-cell detection. It ment to X-ray crystallography. Notably, it is the only method is also evident that solid-state NMR spectroscopy is making that can accurately define atomic structures in solution. headway, extending the applicability of NMR spectroscopy to To date (June 2009) over 5000 NMR structures of proteins study protein atomic structure in fibers, crystals, glasses (here taken to contain 50 or more residues) have been deposited and amorphous formulations. For the immediate future, the at the Protein Data Bank (PDB), whereas the first deposited inclusion of chemical shift information promises to become a structures date back only to 1989. With few exceptions these very powerful addition to structure determination, making use structures have been determined in solution, similar to their of semiempirical relationships as well as ab initio calculations. Recent progress in quantum chemical methods makes it a Groningen Biomolecular Sciences and Biotechnology Institute, possible to derive accurate relationships between calculated University of Groningen, Nijenborgh 4, 9747 AG Groningen, shielding parameters and protein 3D conformation and The Netherlands b Zernike Institute for Advanced Materials, University of Groningen, increases significantly the range of proteins that can be Nijenborgh 4, 9747 AG Groningen, The Netherlands characterized structurally with NMR spectroscopy. Although Frans A. A. Mulder (MSc and M. Filatov (MSc University PhD cum laude from Utrecht of Novosibirsk (Russia), University) was a post-doctoral PhD Institute of Catalysis fellow with Lewis E. Kay at (Novosibirsk, Russia)) was a the University of Toronto, and postdoctoral fellow with Mikael Akke at Lund Univer- Walter Thiel at Zu¨rich Uni- sity. In 2004 he moved to the versity and with Sason Shaik University of Groningen, and at the Hebrew University of in 2006 he was awarded a Jerusalem before working young investigator VIDI grant as an Assistant Professor at from the Netherlands Research the University of Go¨teborg, Organization. In 2005, he Sweden from 2000 till 2005. spent a sabbatical with H. Vogel Since 2005 he has been a at the University of Calgary. Professor of Theoretical Frans A. A. Mulder Current research interests in Michael Filatov Chemistry at the University his group include protein of Groningen (Netherlands). electrostatics, natively unfolded proteins, NMR pulse sequence His research interests focus on the development of accurate development, protein molecular dynamics, and NMR structure quantum chemical computational schemes within the domain of determination of large proteins using bio-synthetic isotope density functional theory and on modeling ground and excited labeling and computational methods. state electronic properties of organic, bio-inorganic and inorganic compounds. 578 | Chem.Soc.Rev., 2010, 39, 578–590 This journal is c The Royal Society of Chemistry 2010 chemical shieldings are very rich in information, owing to their The most easily accessible alternative probes of molecular tensorial character1 we focus primarily on isotropic chemical conformation in proteins are the chemical shifts of 13C and shifts, as these are more relevant for comparison with 15N nuclei. There are two major routes of using the informa- experimental data. tion from chemical shifts: (i) an empirical route based on the observation that similar structures produce similar chemical shifts, and (ii) a first principles modeling of chemical shifts in II. Experimental determination of specific protein secondary structures. three-dimensional protein structures by A. Empirical relationships between chemical shift and NMR spectroscopy structure All the parameters that can be measured by NMR spectro- Chemical shifts are readily obtained for large proteins, and are scopy are sensitive to molecular structure and dynamics and also among the more easily accessible data for proteins in the can be employed as restraints to construct models of the three- solid state. Therefore, by using this information it should be dimensional structures of proteins. The structures of small possible to further expand the reach of NMR spectroscopy in proteins (up to B100 amino acids) have traditionally been structural biology. However, since many factors potentially 1 derived from two-dimensional, homonuclear H NMR contribute to protein chemical shifts it is important to spectroscopy, and were primarily based on extensive lists of establish their relative contributions, and assess their pairwise distances derived from nuclear Overhauser effects independence.3 As an important first step, one needs to define (NOEs), and from dihedral angle restraints derived from a reference state from which all factors are to be counted. In 2 scalar spin–spin couplings (J). The obvious advantage of this practice it is common to define ‘‘random coil’’ chemical shifts approach is that protein material can be isolated from a for short peptides, which are assumed to be disordered, and natural source, and, after purification, subjected to investi- devoid of persistent structure. Random coil chemical shifts gation. However, even a small protein of 100 residues will rely on the specific identity of the side chain, and conforma- contain approximately 800 protons, hence the NMR spectra tional sampling, and have proven very valuable when investi- are highly congested. With increasing size, the number of gating the effects of amino acid sequence on chemical shifts.4 signals that will appear in the same spectral region will become In a second, alternative, approach the chemical shifts of a overwhelming, and this overlap problem becomes prohibitive peptide fragment are obtained from so-called ‘‘coil libraries’’.5 for spectral assignment and structure determination. Multi- In this case, proteins of known structure are used to filter dimensional spectroscopy mitigates this problem somewhat, chemical shift data belonging to regions of regular secondary but many restraints remain ambiguous. structure (a-helices, b-sheets and turns) from those of ‘‘coil’’. This problem can be overcome by making use of additional The resultant library is assumed to represent a generic 13 15 spins in proteins, such as C and N. However, because reference state for disordered peptides, and the formation of of the low natural abundance of the favorable spin-1/2 structure will induce chemical shift changes through, for 13 15 isotopes—1.1% for C and 0.36% for N—this approach example, changes in backbone dihedral angles, hydrogen only became feasible through the use of heterologous protein bonds and ring current shifts of nearby aromatic residues.
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