scholarly journals Analysis of conformational exchange processes using methyl-TROSY-based Hahn echo measurements of quadruple-quantum relaxation

2021 ◽  
Vol 2 (2) ◽  
pp. 777-793
Author(s):  
Christopher A. Waudby ◽  
John Christodoulou
Keyword(s):  
Chemical Shift ◽  
Chemical Exchange ◽  
Relaxation Dispersion ◽  
Conformational Exchange ◽  
Parameter Estimates ◽  
Relaxation Rates ◽  
Exchange Processes ◽  
Methyl Trosy ◽  
Quantum Transitions ◽  
Order Of Magnitude

Abstract. Transverse nuclear spin relaxation is a sensitive probe of chemical exchange on timescales on the order of microseconds to milliseconds. Here we present an experiment for the simultaneous measurement of the relaxation rates of two quadruple-quantum transitions in 13CH3-labelled methyl groups. These coherences are protected against relaxation by intra-methyl dipolar interactions and so have unexpectedly long lifetimes within perdeuterated biomacromolecules. However, these coherences also have an order of magnitude higher sensitivity to chemical exchange broadening than lower order coherences and therefore provide ideal probes of dynamic processes. We show that analysis of the static magnetic field dependence of zero-, double- and quadruple-quantum Hahn echo relaxation rates provides a robust indication of chemical exchange and can determine the signed relative magnitudes of proton and carbon chemical shift differences between ground and excited states. We also demonstrate that this analysis can be combined with established Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion measurements, providing improved precision in parameter estimates, particularly in the determination of 1H chemical shift differences.

scholarly journals Analysis of Conformational Exchange Processes using Methyl-TROSY-Based Hahn Echo Measurements of Quadruple-Quantum Relaxation

2021 ◽  
Author(s):  
Christopher Andrew Waudby ◽  
John Christodoulou
Keyword(s):  
Chemical Shift ◽  
Chemical Exchange ◽  
Relaxation Dispersion ◽  
Conformational Exchange ◽  
Parameter Estimates ◽  
Relaxation Rates ◽  
Exchange Processes ◽  
Methyl Trosy ◽  
Quantum Transitions ◽  
Order Of Magnitude

Abstract. Transverse nuclear spin relaxation is a sensitive probe of chemical exchange on timescales on the order of microseconds to milliseconds. Here we present an experiment for the simultaneous measurement of the relaxation rates of two quadruple-quantum transitions in 13CH3-labelled methyl groups. These coherences are protected against relaxation by intra-methyl dipolar interactions, and so have unexpectedly long lifetimes within perdeuterated biomacromolecules. However, these coherences also have an order of magnitude higher sensitivity to chemical exchange broadening than lower order coherences, and therefore provide ideal probes of dynamic processes. We show that analysis of the static magnetic field dependence of zero-, double- and quadruple-quantum Hahn echo relaxation rates provides a robust indication of chemical exchange, and can determine the signed relative magnitudes of proton and carbon chemical shift differences between ground and excited states. We also demonstrate that this analysis can be combined with established CPMG relaxation dispersion measurements, providing improved precision in parameter estimates, particularly in the determination of 1H chemical shift differences.

scholarly journals Analysis of Conformational Exchange Processes using Methyl-TROSY-Based Hahn Echo Measurements of Quadruple-Quantum Relaxation

2021 ◽  
Author(s):  
Christopher Andrew Waudby ◽  
John Christodoulou
Keyword(s):  
Chemical Shift ◽  
Excited States ◽  
Chemical Exchange ◽  
Relaxation Dispersion ◽  
Conformational Exchange ◽  
Nuclear Spin Relaxation ◽  
Relaxation Rates ◽  
Exchange Processes ◽  
Methyl Trosy

Transverse nuclear spin relaxation can be a sensitive probe of chemical exchange on timescales on the order of microseconds to milliseconds. Here we present an experiment for the simultaneous measurement of the relaxation rates of two four-spin transitions in selectively protonated methyl groups within perdeuterated biomacromolecules, alongside control experiments for measurement of 1H and 13C chemical shift anisotropies. We show that analysis of the static magnetic field dependence of zero-, double- and quadruple-quantum Hahn echo relaxation rates provides a robust indication of chemical exchange and determines the signed relative magnitudes of proton and carbon chemical shift differences between ground and excited states. The analysis can be combined with CPMG relaxation dispersion measurements to provide improved precision, particularly in the determination of 1H chemical shift differences.

scholarly journals Cross-Peaks in Simple 2D NMR Experiments from Chemical Exchange of Transverse Magnetization

2019 ◽  
Author(s):  
Chris Waudby ◽  
Tom Frenkiel ◽  
John Christodoulou
Keyword(s):  
Chemical Shift ◽  
Chemical Exchange ◽  
Exchange Process ◽  
2D Nmr ◽  
Two Dimensional ◽  
One Dimensional ◽  
Exchange Processes ◽  
Rich Information ◽  
Multiple Chemical

Two-dimensional correlation measurements such as COSY, NOESY, HMQC and HSQC experiments are central to small molecule and biomolecular NMR spectroscopy, and commonly form the basis of more complex experiments designed to study chemical exchange occurring during additional mixing periods. However, exchange occurring during chemical shift evolution periods can also influence the appearance of such spectra. While this is often exploited through one-dimensional lineshape analysis ('dynamic NMR'), the analysis of exchange across multiple chemical shift evolution periods has received less attention. Here we report that chemical exchange-induced cross-peaks can arise in even the simplest two-dimensional NMR experiments. These cross-peaks can have highly distorted phases that contain rich information about the underlying exchange process. The quantitative analysis of such peaks, from a single 2D spectrum, can provide a highly accurate characterization of underlying exchange processes.

scholarly journals Revisiting paramagnetic relaxation enhancements in slowly rotating systems: how long is the long range?

2020 ◽  
Author(s):  
Giovanni Bellomo ◽  
Enrico Ravera ◽  
Vito Calderone ◽  
Mauro Botta ◽  
Marco Fragai ◽  
...  
Keyword(s):  
Chemical Exchange ◽  
Protein Structure Determination ◽  
Bulk Water ◽  
Water Proton ◽  
Proton Relaxation ◽  
Relaxation Rates ◽  
Rotating Systems ◽  
Complete Relaxation ◽  
Nuclear Magnetization ◽  
Order Of Magnitude

Abstract. Cross relaxation terms in paramagnetic systems that reorient rigidly with slow tumbling times can increase the effective longitudinal relaxation rates of protons of more than one order of magnitude. This is evaluated by simulating the time evolution of the nuclear magnetization using a complete relaxation matrix approach. The calculations show that the Solomon dependence of the relaxation rates on the metal-proton distance (as r−6) can be incorrect for protons farther than 15 Å from the metal, and thus can originate sizable errors in R1-derived distance restraints used, for instance, for protein structure determination. Furthermore, the chemical exchange of these protons with bulk water protons can enhance the relaxation rate of the solvent protons by far more than expected from the Solomon equation. Therefore, it may contribute significantly to the water proton relaxation rates measured at MRI magnetic fields in the presence of slow-rotating nanoparticles containing paramagnetic ions and a large number of exchangeable surface protons.

scholarly journals Towards autonomous analysis of Chemical Exchange Saturation Transfer experiments using Deep Neural Networks

2021 ◽  
Author(s):  
Gogulan Karunanithy ◽  
Tairan Yuwen ◽  
Lewis E Kay ◽  
D Flemming Hansen
Keyword(s):  
Neural Networks ◽  
Deep Neural Networks ◽  
Chemical Exchange ◽  
Chemical Shifts ◽  
Conformational Exchange ◽  
Chemical Exchange Saturation Transfer ◽  
Saturation Transfer ◽  
Nmr Data ◽  
Exchange Processes ◽  
Fitting Procedures

Macromolecules often exchange between functional states on timescales that can be accessed with NMR spectroscopy and many NMR tools have been developed to characterise the kinetics and thermodynamics of the exchange processes, as well as the structure of the conformers that are involved. However, analysis of the NMR data that report on exchanging macromolecules often hinges on complex least-squares fitting procedures as well as human experience and intuition, which, in some cases, limits the widespread use of the methods. The applications of deep neural networks (DNNs) and artificial intelligence have increased significantly in the sciences, and recently, specifically, within the field of biomolecular NMR, where DNNs are now available for tasks such as the reconstruction of sparsely sampled spectra, peak picking, and virtual decoupling. Here we present a DNN for the analysis of chemical exchange saturation transfer (CEST) data reporting on two- or three-site chemical exchange involving sparse state lifetimes of between approximately 3 - 60 ms, the range most frequently observed via experiment. The work presented here focuses on the 1H CEST class of methods that are further complicated, in relation to applications to other nuclei, by anti-phase features. The developed DNNs accurately predict the chemical shifts of nuclei in the exchanging species directly from anti-phase 1HN CEST profiles, along with an uncertainty associated with the predictions. The performance of the DNN was quantitatively assessed using both synthetic and experimental anti-phase CEST profiles. The assessments show that the DNN accurately determines chemical shifts and their associated uncertainties. The DNNs developed here do not contain any parameters for the end-user to adjust and the method therefore allows for autonomous analysis of complex NMR data that report on conformational exchange.

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