Rapid NMR Data Collection

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Abstract

Rapid data collection is an area of intense research in biomolecular NMR spectroscopy, in particular for high-throughput structure determination in structural genomics. NMR data acquisition and processing protocols for rapidly obtaining high-dimensional spectral information aim at avoiding sampling limited data collection and are reviewed here with emphasis on G-matrix Fourier transform NMR spectroscopy.

Introduction

Multidimensional nuclear magnetic resonance (NMR) spectroscopy is pivotal for pursuing NMR-based structural biology (Cavanagh 1996, Wüthrich 1986). In many instances, it is desirable to obtain multidimensional spectral information as rapidly as possible. First, the costs related to spectrometer usage are reduced, and the throughput of samples per NMR spectrometer can be increased. Second, the requirement for longevity of NMR samples is alleviated. Third, a higher time resolution can be achieved to study dynamic processes by multidimensional spectra. The first two objectives are at the heart of NMR-based structural genomics, which aims at establishing NMR spectroscopy as a powerful tool for exploring protein “fold space” and yielding at least one experimental structure for each family of protein sequence homologues (Montelione et al., 2000).

Fast acquisition of multidimensional spectra is, however, limited by the need to sample (several) indirect dimensions. This restriction can be coined the “NMR sampling problem”: above a threshold at which the measurement time is long enough to ensure a workable signal-to-noise ratio, the sampling of indirect dimensions determines the requirement for instrument time. In this “sampling-limited” data collection regime (Szyperski et al., 2002), valuable instrument time is invested to meet the sampling demand rather than to achieve sufficient “signal averaging.” Hence, techniques to speed up NMR data collection focus on avoiding this regime, that is, they are devised to push data collection into the “sensitivity-limited” regime in order to properly adjust NMR measurement time to sensitivity requirements. In view of the well-known fact that NMR measurement times tend to increase with molecular weight (Fig. 1), rapid sampling approaches for accurate adjustment of measurement times on the one hand and methodology developed to study large systems on the other [e.g., transverse relaxation optimized spectroscopy (Pervushin et al., 1997) or protein deuteration (Gardner and Kay, 1998)] are complementary.

The implementation of rapid data collection protocols avoiding sampling limitations requires that the number of acquired free induction decays (FIDs), i.e., the number of data points sampled in the indirect dimensions, is reduced. Notably, phase-sensitive acquisition of an ND Fourier transform (FT) NMR experiment requires sampling of N−1 indirect dimensions with n1 × n2 × ⋯ × nN−1 complex points, representing 2N−1 × (n1 × n2 × ⋯ × nN−1) FIDs. A steep increase of the minimal measurement time, Tm, with dimensionality results: acquiring 16 complex points in each indirect dimension (with one scan per FID each second) yields Tm(3D) = 0.5 h, Tm(4D) = 9.1 h, Tm(5D) = 12 days, and Tm(6D) = 1.1 years.

When reducing the number of acquired FIDs, the key challenge is to preserve the multidimensional spectral information that can be obtained by conventional linear sampling with appropriately long maximal evolution times in all indirect dimensions. Moreover, trimming the number of sampled data points may in turn require processing techniques that complement, or replace, widely used Fourier transformation of time domain data. Hence, we shall review approaches to reduce the sampling demand as well as associated processing techniques. To document the impact of rapid NMR data sampling for high-throughput structure determination, we shall present a brief survey of the application of a specific fast data acquisition technique, that is, reduced-dimensionality NMR spectroscopy, in the Northeast Structural Genomics Consortium (http:⧸⧸www.nesg.org).

Section snippets

Rapid NMR Data Collection

Currently available approaches to accelerate NMR data collection in biological NMR spectroscopy are summarized in Table I. One could classify as “basic” those that require only adjustment of acquisition parameter(s), while modification of the radiofrequency (rf) pulse scheme and⧸or more sophisticated data processing protocols are required for “advanced” approaches.

Processing of Rapidly Sampled NMR Data Sets

In this section, we shall briefly survey processing protocols that are used in conjunction with the rapid sampling protocols (Table I) described in the previous section.

Application of Reduced-Dimensionality NMR Spectroscopy in Structural Genomics

Rapid NMR data acquisition is critical in structural genomics projects in which 3D structures of proteins are to be solved in a high-throughput manner. It has been proposed at the outset of establishing structural genomics consortia that RD NMR will play an important role in NMR-based structural genomics (Montelione et al., 2000). In fact, solution of the NMR sampling problem is a prerequisite to optimally adjust measurement times (Fig. 1). RD and GFT NMR spectroscopy are particularly

Conclusions

The development of techniques for rapid acquisition of multidimensional NMR data is a rapidly growing field. In view of the fact that increasing spectrometer sensitivity can be used to approach larger system and⧸or to speed up data collection, such methodology is pivotal to take best advantage of costly high-field NMR equipment. Moreover, the design of rapid sampling protocols shall allow integration with technology for automated data analysis. It currently appears that the use of RD⧸GFT NMR

Acknowledgements

Our research was supported by the Protein Structure Initiative of the National Institutes of Health (PM GM62413-01) and the National Science Foundation (MCB 0075773). We thank our colleagues of the Northeast Structural Genomics Consortium (NESGC), in particular Gaetano Montelione, for fruitful discussions.

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