Improving spectral resolution in biological solid-state NMR using phase-alternated rCW heteronuclear decoupling

Chemical Physics Letters 635 (2015) 339–344

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Improving spectral resolution in biological solid-state NMR using phase-alternated rCW heteronuclear decoupling Asif Equbal a , Morten Bjerring a , P.K. Madhu b,c,∗ , Niels Chr. Nielsen a,∗∗ a Center for Insoluble Protein Structures, Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark b Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India c TIFR Centre for Interdisciplinary Sciences, 21 Brundavan Colony, Narsingi, Hyderabad 500075, India

a r t i c l e

i n f o

Article history: Received 25 May 2015 In final form 6 July 2015 Available online 14 July 2015

a b s t r a c t The successful application of solid-state NMR spectroscopy for structural study of biological macromolecules requires high spectral resolution. In presence of abundant 1 H spins, the resolution of the prevailing 13 C or 15 N chemical shift encoding experiments critically depends on the availability of efficient and robust heteronuclear decoupling methods in addition to the use of high-field instrumentation and fast sample spinning. Robustness of the decoupling method towards alterations in amplitude/offset of radio frequency fields due to varying sample states is important to ensure recording of spectra with high resolution over long sampling periods for insensitive samples. Here, we present a phase-alternated refocused continuous-wave decoupling method offering better resolution, easier setup, and higher robustness than previous methods. Improved decoupling is in part ascribed to more efficient cancellation of the residual heteronuclear, 1 H–13 C, dipolar coupling interactions which are induced by homonuclear, 1 H–1 H, dipolar coupling interactions. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Solid-state NMR spectroscopy is becoming an increasingly important tool for the atomic scale investigation of biological macromolecules in complex heterogenous environment, including protein complexes, amyloid fibrils, and membrane proteins [1–14]. The growing capability of the method is ascribed to development of high-field instrumentation, fast sample spinning probes, new isotope-labelling procedures, and design of efficient pulse sequences for manipulating the spins to ensure high resolution and establishment of structural parameters. The spectral resolution may be improved using higher static magnetic fields through linear scaling of isotropic chemical-shift interactions. This applies to the limit where residual anisotropic nuclear spin interactions become the critical factor, in which case coherent averaging through fast magic-angle spinning (MAS) and radio-frequency (rf) irradiation

∗ Corresponding author at: Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India. ∗∗ Corresponding author at: Center for Insoluble Protein Structures, Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. E-mail addresses: [email protected] (P.K. Madhu), [email protected] (N.Chr. Nielsen). http://dx.doi.org/10.1016/j.cplett.2015.07.008 0009-2614/© 2015 Elsevier B.V. All rights reserved.

is needed. In the most typical situation with abundant 1 H spins present, it is difficult to record high-resolution 1 H spectra implying that spectral resolution is typically achieved through detection of 13 C and 15 N resonances in 13 C, 15 N-isotopically labelled samples. In this case, it is crucial to invoke efficient heteronuclear decoupling to reduce effects from dipolar couplings between the low- spin and protons and indirect effects from homonuclear 1 H–1 H interactions such as higher order and cross terms. With the aim of obtaining high-resolution spectra of low- nuclei in solid-state NMR spectroscopy, a great variety of heteronuclear decoupling sequences have been developed over the years which markedly increases the resolution relative to bruteforce continuous-wave (CW) decoupling [15–32]. These include powerful methods such as two-pulse phase-modulation (TPPM) [17], its supercycled variant SPINAL [20], its frequency-swept variant SWf -TPPM [26], XiX [16,22], and lately refocussed continuous wave (rCW) [28,29,31] decoupling. In general, although overall improving spectral resolution tremendously, such sequences are not straightforward to set up for optimal performance, and often involves optimization of one or more parameters for a given experimental condition. With focus on biological macromolecules in native environment, including mixtures of proteins, lipids, small molecule constituents, water, and salts, it becomes exceedingly difficult to ensure the best decoupling conditions as

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obtained peak height observed for the 13 C˛ resonance of U–13 Cglycine as a function of the phases  and  of the CW and  pulse elements, respectively, in the second rCW block in the new pulse scheme. The pulse sequence, initialized with a standard ramped CP element [33], used for this optimization is shown in Figure 1b. During the optimization, the duration of the timing parameter,  A , was adjusted slightly away from rotor synchronization (i.e., the rotor cycle period,  r ) following the recommendations presented recently [31]. From the plots, it is evident that the phase-alternated scheme with  = 180◦ and  = 90◦ gives most efficient heteronuclear dipolar decoupling. This leads to a pulse schematic with a rCWA element concatenated with a CW phase-alternated rCWA element to form the phase-alternated sequence rCWApA in Figure 1c. Altering/inverting the phases of the CW blocks in second rCWA block helps in cancelling some of the residual dipolar term and thereby leads to improved decoupling performance. It is worth mentioning here that under ideal  pulses case (i.e., when  is infinitesimally short), phase, , can be 90◦ or 270◦ . In this scenario, the additional block is a supercycled version of the rCWA with  = 270. However, non-ideal  or finite  pulses seem to be performing better when  = 90◦ . 2.2. Ease of optimization

Figure 1. (a) The basic rCWA decoupling element. Timing parameter,  A =  cw + 0.5  . (b) The pulse schematic used for experimental optimization of the phase-alternated decoupling sequence (top-right). (c) The optimized, phase-alternated rCWApA sequence. (d) Experimental optimization of phases of CW and  pulse elements in the second rCWA block of the scheme shown in (b). The underlying spectra were recorded for U–13 C-glycine using a 400 MHz NMR instrument under conditions of  A = 0.98 r , 1 = 125 kHz, and r = 30 kHz.

Addressing the important aspect of robustness and convenience in optimization, Figure 2 shows experimental peak heights obtained for the 13 C˛ resonance of U–13 C-glycine (uniformly 13 C labeled glycine) obtained in case of rCWApA decoupling as a function of  A / r (horizontal axis) and the rf amplitude 1 (vertical axis) for MAS frequencies of (a) 20 kHz and (b) 30 kHz. Figure 2c and d shows projections out of the contour plots in Figure 2a and b, respectively, for different values of 1 . All plots clearly reveal that efficient decoupling can be obtained by setting  A around 0.98  r for any given rf amplitude and spinning frequency. Such a generality implies that efficient decoupling can be obtained without the need for optimization. 2.3. Effect of high rf amplitude  pulse

optimizations on model samples do not necessarily reflect the conditions in the real sample and finding efficient decoupling condition on the sample itself may be highly time consuming or impossible. Furthermore, sample spinning in extended periods of data acquisition may lead to dehydration and susceptibility changes eventually altering the performance of decoupling during measurements. To address these challenges, we here introduce a simple phase-alternated rCW decoupling scheme demonstrating superior decoupling performance, improved tolerance to experimental parameters, and which virtually does not require any parameter optimization for efficient decoupling under varying experimental conditions.

A vital element in the rCW sequences is the refocusing  pulse. The  pulse facilitates averaging of heteronuclear dipole–dipole couplings and indirect effects from anisotropic 1 H chemical shielding interactions. We have found that application of high rf amplitude or shorter  pulse can lead to further improved decoupling efficiency. Figure 3 compares decoupling performance of rCWApA for different rf amplitudes of the  pulse while maintaining the same rf amplitude of the CW blocks in the rCWApA sequence. It can be seen from the figure that with increased amplitude of the  pulse, an enhancement of up to 10% can be easily obtained. It is in the present context important to mention that increasing rf amplitude does not change the optimal decoupling condition. Efficient decoupling can always be obtained for  A close to 0.98 r .

2. Results and discussion

2.4. Decoupling efficiency

2.1. Phase-alternated rCW

We discussed above that the sequence is robust, providing decoupling without optimization. The most important remaining point is the absolute decoupling efficiency. To address this point, Figure 4 compares the decoupling performance of the phasealternated scheme, rCWApA , with state-of-the art sequences like TPPM, SPINAL-64, SWf -TPPM, and rCWA . The figure shows normalized peak heights for the 13 C˛ resonance of U–13 C-glycine obtained for the various decoupling sequences using a 700 MHz NMR instrument with the conditions 1 = 90 kHz and r = 18 kHz. Clearly, the most efficient decoupling was achieved in case of rCWApA with high

Among current heteronuclear decoupling sequences, the rCW schemes [28,31] appear particularly promising in terms of efficiency, robustness, and ease in setup. Aimed at improving these features, we have here taken the simple rCWA element [31] (Figure 1a) as basis and experimentally optimized the decoupling efficiency through concatenation with a phase-altered variant of this element. The remarkable outcome of this simple operation is seen in the contour plot in Figure 1d showing experimentally

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Figure 2. (a) Normalized peak height observed for the 13 C˛ resonance of U–13 C-glycine as a function of  A / r and the rf amplitude 1 . The spectra were recorded using a 400 MHz NMR instrument with r being 20 and 30 kHz in (a) and (b), respectively. Projections out of the contour plots in (a) and (b) are shown in (c) and (d), respectively. Green, red, and black colors correspond to 1 = 145, 105, and 75 kHz, respectively (equal amplitude for CW and -pulse irradiation). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this Letter.)

rf amplitude (210 kHz) with the  pulse. Using the same amplitude for the CW and the  pulse (90 kHz), the rCWApA sequence also stands out as more efficient than the other methods. In both cases of the rCWApA sequence, the timing parameter  A was around 0.98 r and virtually no optimization was required to get the best decoupling conditions. Other sequences like TPPM, SPINAL64, SWf TPPM, and even rCWA required optimization and still turned out to be less efficient than the rCWApA sequence. Optimum decoupling conditions for these sequences can be found in the supplementary information. Extending the comparison to biological macromolecules, Figure 5a and b compares the performance of SPINAL-64 and rCWApA decoupling for a protein sample, GB1 (ˇ1 immunoglobulin

Normalized intensity

1.0

binding domain of protein G) [34]. Figure 3c shows 13 C–13 C correlation spectrum of GB1 from a DARR [35,36] experiment using rCWApA in the free precession periods, while Figure 3d shows overlaid slices from DARR experiments recorded using SPINAL-64 and rCWApA decoupling. The spectra were recorded using a 700 MHz NMR instrument with r and 1 set to 18 and 90 kHz, respectively. In case of SPINAL-64, optimization was carefully conducted to ensure optimal decoupling, while rCWApA decoupling was accomplished without any optimization. Even without optimization the spectra reveals increases of up to 30% in the peak heights using rCWApA decoupling compared to SPINAL-64 decoupling. We note that a large set of comparisons consistently signify the rCWApA sequence to be performing superior in decoupling, especially for spinning frequencies larger than 15 kHz, where 1 /r ratio cannot be set to a large value.

2.5. Robustness towards experimental parameters

0.6

0.2 0.5

1.0

1.5

2.0

Figure 3. Decoupling performance of rCWApA for different rf amplitudes, 1 , for the refocusing  pulses. The experiments were recorded for 13 C˛ in U–13 C-glycine under conditions of  A = 0.98 r , 1cw = 90 kHz, and r = 25 kHz. Black, red, and green color correspond to 90, 110, and 210 kHz for 1 , respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this Letter.)

While efficiency and ease of optimization are definitely important characteristics, the robustness of decoupling towards experimental parameters like rf carrier frequency and rf amplitude is also highly important, with the latter being particularly important for lossy samples. One of the most distinct advantages of the rCWApA sequence is that its optimum decoupling condition does not depend on the rf amplitude unlike TPPM, SWf -TPPM, and SPINAL-64 methods. This makes the sequence more tolerant towards mismatch or deviation in rf irradiation. To illustrate this important advantage, Figure 6a shows the decoupling performance

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1.0 0.6 0.2 (

1

rCWApA =210kHz)

rCWApA (

1

rCWA =210kHz)

SPINAL-64

TPPM

SWf-TPPM

ppm

Figure 4. Normalized 13 C˛ U–13 C-glycine spectra recorded using different decoupling sequences under the experimental conditions of r = 18 kHz and 1 = 90 kHz.

(a)

(b)

20 30 40 50 60 70 70

60

50

40

30

20 ppm

60

50

40

30

20 ppm

Figure 5. 2D DARR spectra showing 13 C–13 C correlations for GB1 recorded using rCWApA decoupling under the experimental conditions of r = 18 kHz and 1 = 90 kHz (equal amplitude for CW and -pulse irradiation). (b) Projections out of DARR spectra obtained using rCWApA (blue) and SPINAL-64 (red) decoupling. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this Letter.)

Figure 6. (a) Normalized peak height of the 13 C˛ resonance of U–13 C-glycine as a function of deviation in pulse length from the optimum conditions in case of TPPM and rCWApA decoupling (r = 25 kHz and 1 = 90 kHz). The optimum conditions of TPPM and rCWApA decoupling are given in supplementary information. (b) Experimental performance of rCWApA decoupling as function of the rf field offset for the 13 C˛ resonance of U–13 C-glycine under conditions of r =18 kHz and 1 = 100 kHz. (c) Normalized peak height of the 13 C˛ resonance of U–13 C-glycine as a function of flip angle of the refocusing pulse under experimental conditions of r = 18 kHz and 1 = 100 kHz. (d) Numerically simulated (using SIMPSON) peak heights for the 13 C resonance of a 13 CH2 group under four different nuclear spin–spin interactions and rCWApA decoupling with r = 20 kHz, 1 = 105 kHz. The amplitude of the  pulse was set to 210 kHz.

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of TPPM and rCWApA upon varying the lengths of the pulses in each of the sequence from their optimum value. In case of TPPM, even a small deviation of 0.2 ␮s in the pulse length can lead to severe drop in the decoupling performance. Compared to TPPM, rCWApA decoupling is much more tolerant. Deviation in optimum condition hardly leads to any decline in the decoupling performance. This may render rCWApA decoupling the method of choice for multidimensional experiments where a small fluctuations in effective rf power with time are unavoidable. As evident from Figure 6b, the rCWApA scheme is also very robust towards offsets in the rf carrier frequencies as mapped in terms of peak height for the 13 C˛ resonance of U–13 C-glycine upon varying the 1 H carrier frequency from −10 to +10 ppm. For these experiments, the spinning frequency was set to 18 kHz and the rf field amplitude to 100 kHz. It is seen that even for an rf offset of ±10 ppm, the drop in peak height is around 20% using rCWApA decoupling. This is better than observed for other sequences like SPINAL-64, TPPM, and SWf -TPPM where performance goes down to around 50%. The robustness of rCWApA towards deviation in the flip angle of the refocusing- pulse is explored in Figure 6c showing the normalized peak intensity of 13 C of U–13 C-glycine as a function of flip angle of the refocusing ˛ pulses in rCWApA while keeping the timing condition of the decoupling fixed to  A = 0.98 r . Deviation of 60◦ from the optimum value led to less than 10% attenuation in the observed peak height. 2.6. Effect of various anisotropic interactions To obtain insight into the decoupling mechanism of the rCWApA sequence, we undertook numerical investigation of the decoupling efficiency under influence of different kinds of nuclear spin interactions using the SIPMSON simulation package [37,38] with spin system parameters obtained using SIMMOL [39]. From literature, it is known that the heteronuclear decoupling sequences like XiX, are predominantly affected by residual dipolar coupling terms arising from the cross-term between homonuclear 1 H–1 H and heteronuclear 1 H–13 C dipole–dipole coupling interactions. The results from the numerical simulations, shown in Figure 6d, reveal that decoupling performance of rCWApA is not hampered by the presence of homonuclear dipolar coupling interaction. This means that the residual dipolar coupling terms arising from the cross-term between homonuclear 1 H–1 H and heteronuclear 1 H–13 C dipole–dipole coupling interactions are canceled in rCWApA sequence. Apart from this, the effect of the cross term between 1 H chemical-shift anisotropy (CSA) and heteronuclear 1 H–13 C dipolar coupling interactions is also very small which are dominant in sequences like TPPM and its variants. This implies that rCWApA decoupling has another very important advantage over other sequences for wide range of spin systems/samples displaying strong anisotropic interactions not least under conditions of high static magnetic fields. 3. Methods: experimental and numerical The experiments presented here were carried out on a Bruker Avance III wide bore 700 MHz NMR spectrometer (Bruker Biospin, Rheinstetten) and Bruker Avance II wide bore 400 MHz NMR spectrometer (Bruker Biospin, Rheinstetten). All the experiments were performed using a Bruker 2.5 mm XYZ triple-resonance probe. For all the experiments, the initial polarization to 13 C was transferred from protons using ramped-amplitude cross polarization (CP) [33]. All simulations were performed using the open source SIMPSON [37,38] simulation software package for typical parameters of a CH2 spin system (assuming conditions of a 700 MHz NMR spectrometer): ıCSA = −2450 Hz, ıCSA = 0 Hz, CSA = 0 kHz, ıiso = 0 Hz, H C H1 iso iso D D /2 = −21.3 kHz, ıH2 = 200 Hz, ıC = 0 Hz, ωHC /2 = −23.3 kHz, ωHH

J

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J

ωHC /2 = 0 Hz, and ωHH /2 = 0 Hz. These anisotropic tensor orientations were obtained using SIMMOL [39]. Powder averaging was mimicked with the REPULSION scheme [40] employing ˛CR , ˇCR 100 crystallite orientations and 12  CR angles. 4. Conclusions We conclude that the proposed rCWApA decoupling scheme is a good candidate for heteronuclear dipolar decoupling in biological solid-state NMR in terms of efficiency, ease of setup, and robustness towards experimental parameters. Good decoupling performance virtually requires no optimization for any given sample and even covers a wide range of experimental conditions. Unlike most state-of-the-art decoupling methods, the performance of rCWApA decoupling is also largely unaffected by the presence of strong homonuclear dipolar coupling interactions overall thereby rendering rCWApA decoupling an ideal choice for efficient and robust decoupling specially for insensitive samples including biological macromolecules in native heterogeneous environment. Acknowledgements The project was supported by grants from the Danish National Research Foundation (DNRF59) and the European Commission under the Seventh Framework Programme (FP7), contract Bio-NMR 261863. We thank Dr. Zdenek Tosner for assistance with the SIMSPON implementation. Appendix A. Supplementary data Supplementary data associated with this Letter can be found, in the online version, at http://dx.doi.org/10.1016/j.cplett.2015.07. 008 References [1] M. Etzkorn, S. Martell, O.C. Andronesi, K. Seidel, M. Engelhard, M. Baldus, Angew. Chem. Int. Ed. 46 (2007) 459. [2] C. Wasmer, A. Lange, H. Van Melckebeke, A.B. Siemer, R. Riek, B.H. Meier, Science 319 (2008) 1523. [3] Y. Li, D.A. Berthold, R.B. Gennis, C.M. Rienstra, Protein Sci. 17 (2008) 199. [4] M. Hiller, V.A. Higman, S. Jehle, B.J. van Rossum, W. Kühlbrandt, H. Oschkinat, J. Am. Chem. Soc. 130 (2008) 408. [5] T. Vosegaard, M. Kamihira-Ishijima, A. Watts, N.C. Nielsen, Biophys. J. 94 (2008) 241. [6] J.T. Nielsen, M. Bjerring, M.D. Jeppesen, R.O. Pedersen, J.M. Pedersen, K.L. Hein, T. Vosegaard, T. Skrydstrup, D.E. Otzen, N.C. Nielsen, Angew. Chem. Int. Ed. 48 (2009) 2118. [7] A.C. Sivertsen, M.J. Bayro, M. Belenky, R.G. Griffin, J. Herzfeld, J. Mol. Biol. 387 (2009) 1032. [8] S.D. Cady, K. Schmidt-Rohr, J. Wang, C.S. Soto, W.F. DeGrado, Nature 463 (2010) 689. [9] A. Loquet, N.G. Sgourakis, R. Gupta, K. Giller, D. Riedel, C. Goosmann, C. Griesinger, M. Kolbe, D. Baker, S. Becker, A. Lange, Nature 486 (2012) 276. [10] N.V. Kulminskaya, M. Pedersen, M. Bjerring, J. Underhaug, M. Miller, N.-U. Frigaard, J.T. Nielsen, N.C. Nielsen, Angew. Chem. Int. Ed. 51 (2012) 6891. [11] J. Lu, W. Qiang, W. Yau, C.D. Schwieters, S.C. Meredith, R. Tycko, Cell 154 (2013) 1257. [12] B. Sarkar, V.S. Mithu, B. Chandra, A. Mandal, M. Chandrakesan, D. Bhowmik, P.K. Madhu, S. Maiti, Angew. Chem. Int. Ed. 53 (2014) 6888. [13] A.K. Schütz, T. Vagt, M. Huber, O.Y. Ovchinnikova, R. Cadalbert, J. Wall, P. Güntert, A. Böckmann, R. Glockshuber, B.H. Meier, Angew. Chem. Int. Ed. 54 (2015) 331. [14] C. Lendel, M. Bjerring, A. Dubnovitsky, R.T. Kelly, A. Filippov, O.N. Antzutkin, N. Oleg, N.C. Nielsen, T. Härd, Angew. Chem. Int. Ed. 53 (2014) 12756. [15] A.L. Bloom, J.N. Shoolery, Phys. Rev. 97 (1955) 1261. [16] P. Tekely, P. Palmas, D. Canet, J. Magn. Reson. A 107 (1994) 129. [17] A.E. Bennett, C.M. Rienstra, M. Auger, K.V. Lakshmi, R.G. Griffin, J. Chem. Phys. 103 (1995) 6951. [18] Z.H. Gan, R.R. Ernst, Solid State Nucl. Magn. Reson. 8 (1997) 153. [19] M. Edén, M.H. Levitt, J. Chem. Phys. 111 (1999) 1511. [20] B.M. Fung, A.K. Khitrin, K. Ermolaev, J. Magn. Reson. 142 (2000) 97. [21] K. Takegoshi, J. Mizokami, T. Terao, Chem. Phys. Lett. 341 (2001) 540. [22] A. Detken, E.H. Hardy, M. Ernst, B.H. Meier, Chem. Phys. Lett. 356 (2002) 298.

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