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An expectation/maximization nuclear vector replacement algorithm for automated NMR resonance assignments

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Abstract

We report an automated procedure for high-throughput NMR resonance assignment for a protein of known structure, or of an homologous structure. Our algorithm performs Nuclear Vector Replacement (NVR) by Expectation/Maximization (EM) to compute assignments. NVR correlates experimentally-measured NH residual dipolar couplings (RDCs) and chemical shifts to a given a priori whole-protein 3D structural model. The algorithm requires only uniform 15N-labelling of the protein, and processes unassigned HN-15N HSQC spectra, HN-15N RDCs, and sparse HN-HN NOE's (d NNs). NVR runs in minutes and efficiently assigns the (HN,15N) backbone resonances as well as the sparse d NNs from the 3D 15N-NOESY spectrum, in O(n 3) time. The algorithm is demonstrated on NMR data from a 76-residue protein, human ubiquitin, matched to four structures, including one mutant (homolog), determined either by X-ray crystallography or by different NMR experiments (without RDCs). NVR achieves an average assignment accuracy of over 99%. We further demonstrate the feasibility of our algorithm for different and larger proteins, using different combinations of real and simulated NMR data for hen lysozyme (129 residues) and streptococcal protein G (56 residues), matched to a variety of 3D structural models. Abbreviations: NMR, nuclear magnetic resonance; NVR, nuclear vector replacement; RDC, residual dipolar coupling; 3D, three-dimensional; HSQC, heteronuclear single-quantum coherence; HN, amide proton; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; d NN, nuclear Overhauser effect between two amide protons; MR, molecular replacement; SAR, structure activity relation; DOF, degrees of freedom; nt., nucleotides; SPG, Streptococcal protein G; SO(3), special orthogonal (rotation) group in 3D; EM, Expectation/Maximization; SVD, singular value decomposition.

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Authors and Affiliations

  1. Dartmouth Computer Science Department, Hanover, NH, 03755, USA

    Christopher James Langmead

  2. Dartmouth Center for Structural Biology and Computational Chemistry, Hanover, NH, 03755, USA

    Bruce Randall Donald

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  1. Christopher James Langmead
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  2. Bruce Randall Donald
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Correspondence to Bruce Randall Donald.

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This work is supported by grants to B.R.D. from the National Institutes of Health (GM-65982) and the National Science Foundation (IIS-9906790, EIA-0305444, and EIA-9802068)

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Langmead, C.J., Donald, B.R. An expectation/maximization nuclear vector replacement algorithm for automated NMR resonance assignments. J Biomol NMR 29, 111–138 (2004). https://doi.org/10.1023/B:JNMR.0000019247.89110.e6

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