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Characterizing micro-to-millisecond chemical exchange in nucleic acids using off-resonance R1? relaxation dispersion.

ABSTRACT: This review describes off-resonance R1? relaxation dispersion NMR methods for characterizing microsecond-to-millisecond chemical exchange in uniformly 13C/15N labeled nucleic acids in solution. The review opens with a historical account of key developments that formed the basis for modern R1? techniques used to study chemical exchange in biomolecules. A vector model is then used to describe the R1? relaxation dispersion experiment, and how the exchange contribution to relaxation varies with the amplitude and frequency offset of an applied spin-locking field, as well as the population, exchange rate, and differences in chemical shifts of two exchanging species. Mathematical treatment of chemical exchange based on the Bloch-McConnell equations is then presented and used to examine relaxation dispersion profiles for more complex exchange scenarios including three-state exchange. Pulse sequences that employ selective Hartmann-Hahn cross-polarization transfers to excite individual 13C or 15N spins are then described for measuring off-resonance R1?(13C) and R1?(15N) in uniformly 13C/15N labeled DNA and RNA samples prepared using commercially available 13C/15N labeled nucleotide triphosphates. Approaches for analyzing R1? data measured at a single static magnetic field to extract a full set of exchange parameters are then presented that rely on numerical integration of the Bloch-McConnell equations or the use of algebraic expressions. Methods for determining structures of nucleic acid excited states are then reviewed that rely on mutations and chemical modifications to bias conformational equilibria, as well as structure-based approaches to calculate chemical shifts. Applications of the methodology to the study of DNA and RNA conformational dynamics are reviewed and the biological significance of the exchange processes is briefly discussed.

SUBMITTER: Rangadurai A

PROVIDER: S-EPMC6727989 | biostudies-literature | 2019 Jun - Aug

REPOSITORIES: biostudies-literature

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Characterizing micro-to-millisecond chemical exchange in nucleic acids using off-resonance R1ρ relaxation dispersion.

Rangadurai Atul A Szymaski Eric S ES Kimsey Isaac J IJ Shi Honglue H Al-Hashimi Hashim M HM

Progress in nuclear magnetic resonance spectroscopy 20190511

This review describes off-resonance R1ρ relaxation dispersion NMR methods for characterizing microsecond-to-millisecond chemical exchange in uniformly 13C/15N labeled nucleic acids in solution. The review opens with a historical account of key developments that formed the basis for modern R1ρ techniques used to study chemical exchange in biomolecules. A vector model is then used to describe the R1ρ relaxation dispersion experiment, and how t ...[more]

PMID: 31481159

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Project description:BackgroundR1ρ (or spin-lock) imaging is prone to artifacts arising from field inhomogeneities that may impact the R1ρ quantification. Previous research has proposed two types of method to manage the artifacts in continuous-wave constant amplitude spin-lock, one is based on the composite block pulses to compensate for the field imperfections, another category uses adiabatic pulses in the R1ρ pre-pulse to excite and reverse the magnetization (named adiabatic prepared approach). Although both methods have proved their efficiency in alleviating artifacts, we observed that the adiabatic pulse approach could produce much lower R1ρ dispersion in human knee cartilage than the block pulse method (characterized by the R1ρ difference ∆R1ρ =11.4 Hz (from spin-lock field 50 to 500 Hz) for the block pulse method vs. ∆R1ρ =4.5 Hz for the adiabatic pulse approach). Prompted by this observation, the purpose of this study was to investigate the underlying factors that may affect the R1ρ dispersion through numerical simulations based on the two-pool exchanging Bloch-McConnell equations.MethodsThe effects of free water pool size Pa (from 0.80 to 0.95), chemical exchange rate kb (from the bound to free water pool, ranged from 500 to 3,000 Hz), adiabatic pulse duration Tp (from 5.0 to 25 ms), and the chemical shift of the bound pool ppmb (from 1.0 to 5.0 ppm) were examined on the degree of the R1ρ dispersion for the two R1ρ imaging methods.ResultsIn general, the greater the ppmb, kb, Tp, and the smaller Pa, the more significant difference in R1ρ dispersion between the block and adiabatic approaches, with the dispersion curve of the adiabatic method becoming flatter.ConclusionsThe adiabatic prepared approach may compromise the R1ρ dispersion, the effect is determined by the combination of the tissue and radiofrequency (RF) pulse properties. It is suggested that care should be taken when using the adiabatically prepared approach to study R1ρ dispersion.

Project description:BackgroundFast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T1ρ relaxation pathway. In this study, we present an improved quantification method for T1ρ using a newly derived formalism of a T1ρ* relaxation pathway.MethodsThe new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T1ρ mapping in mice. Here, the impact of the breath dependent spin recovery time Trec on the quantification results was examined in detail.ResultsSimulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from - 7.4% to - 0.97%. In vivo, a correlation of uncorrected T1ρ with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T1ρ values in different animals was reduced by at least 39%.ConclusionThe suggested quantification formalism enables fast and precise myocardial T1ρ quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results.

Dataset Information

Characterizing micro-to-millisecond chemical exchange in nucleic acids using off-resonance R1? relaxation dispersion.

Publications

Characterizing micro-to-millisecond chemical exchange in nucleic acids using off-resonance R<sub>1ρ</sub> relaxation dispersion.

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