Molecular-Level Insights into the NMR Relaxivity of Gadobutrol Using Quantum and Classical Molecular Simulations

Thiago J. Pinheiro dos Santos; Carla C. Fraenza; Giselle de Araujo Lima e Souza; Emilia Pelegano-Titmuss; Dilipkumar N. Asthagiri; Steven G. Greenbaum; Walter G. Chapman; Philip M. Singer

doi:10.1021/cbmi.4c00080

Molecular-Level Insights into the NMR Relaxivity of Gadobutrol Using Quantum and Classical Molecular Simulations

Thiago J. Pinheiro dos Santos, Carla C. Fraenza, Giselle de Araujo Lima e Souza, Emilia Pelegano-Titmuss, Dilipkumar N. Asthagiri, Steven G. Greenbaum, Walter G. Chapman, Philip M. Singer

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Abstract

MRI is an indispensable diagnostic tool in modern medicine; however, understanding the molecular-level processes governing NMR relaxation of water in the presence of MRI contrast agents remains a challenge, hindering the molecular-guided development of more effective contrast agents. By using quantum-based polarizable force fields, the first-of-its-kind molecular dynamics (MD) simulations of Gadobutrol are reported where the ¹H NMR longitudinal relaxivity r₁ of the aqueous phase is determined without any adjustable parameters. The MD simulations of r₁ dispersion (i.e., frequency dependence) show good agreement with measurements at frequencies of interest in clinical MRI. Importantly, the simulations reveal key insights into the molecular level processes leading to r₁ dispersion by decomposing the NMR dipole-dipole autocorrelation function G(t) into a discrete set of molecular modes, analogous to the eigenmodes of a quantum harmonic oscillator. The molecular modes reveal important aspects of the underlying mechanisms governing r₁, such as its multiexponential nature and the importance of the second eigenmodal decay. By simply analyzing the MD trajectories on a parameter-free approach, the Gadobutrol simulations show that the outer-shell water contributes ∼50% of the total relaxivity r₁ compared to the inner-shell water, in contrast to simulations of (nonchelated) gadolinium-aqua where the outer shell contributes only ∼15% of r₁. The deviation between simulations and measurements of r₁ below clinical MRI frequencies is used to determine the low-frequency electron-spin relaxation time for Gadobutrol, in good agreement with independent studies.

Original language	English
Journal	Chemical and Biomedical Imaging
DOIs	https://doi.org/10.1021/cbmi.4c00080
State	Accepted/In press - 2025

Funding

The authors thank Dr. Phillip Stallworth (Hunter College) for technical assistance with setting up the relaxation measurements, and Dr. Arjun Valiya Parambathu for the insightful discussions on the simulations. The authors also thank the Ken Kennedy Institute, the Rice University Creative Ventures Fund (Faculty Initiatives Fund), and the Robert A. Welch Foundation for the financial support. The authors gratefully acknowledge the U.S. Department of Energy for supporting the research at Oak Ridge National Laboratory under the contract DE-AC05-00OR22725 to UT-Battelle, LLC. This manuscript has been authored by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the US Department of Energy (DOE). The US government retains and the publisher, by accepting the article for publication, acknowledges that the US government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ).

Keywords

Gadobutrol
MRI contrast agents
Molecular Dynamics Simulations
NMR dispersion

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10.1021/cbmi.4c00080

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@article{22c5fd33bc56471fbeec9d1ac047f004,

title = "Molecular-Level Insights into the NMR Relaxivity of Gadobutrol Using Quantum and Classical Molecular Simulations",

abstract = "MRI is an indispensable diagnostic tool in modern medicine; however, understanding the molecular-level processes governing NMR relaxation of water in the presence of MRI contrast agents remains a challenge, hindering the molecular-guided development of more effective contrast agents. By using quantum-based polarizable force fields, the first-of-its-kind molecular dynamics (MD) simulations of Gadobutrol are reported where the 1H NMR longitudinal relaxivity r1 of the aqueous phase is determined without any adjustable parameters. The MD simulations of r1 dispersion (i.e., frequency dependence) show good agreement with measurements at frequencies of interest in clinical MRI. Importantly, the simulations reveal key insights into the molecular level processes leading to r1 dispersion by decomposing the NMR dipole-dipole autocorrelation function G(t) into a discrete set of molecular modes, analogous to the eigenmodes of a quantum harmonic oscillator. The molecular modes reveal important aspects of the underlying mechanisms governing r1, such as its multiexponential nature and the importance of the second eigenmodal decay. By simply analyzing the MD trajectories on a parameter-free approach, the Gadobutrol simulations show that the outer-shell water contributes ∼50\% of the total relaxivity r1 compared to the inner-shell water, in contrast to simulations of (nonchelated) gadolinium-aqua where the outer shell contributes only ∼15\% of r1. The deviation between simulations and measurements of r1 below clinical MRI frequencies is used to determine the low-frequency electron-spin relaxation time for Gadobutrol, in good agreement with independent studies.",

keywords = "Gadobutrol, MRI contrast agents, Molecular Dynamics Simulations, NMR dispersion",

author = "\{Pinheiro dos Santos\}, \{Thiago J.\} and Fraenza, \{Carla C.\} and \{de Araujo Lima e Souza\}, Giselle and Emilia Pelegano-Titmuss and Asthagiri, \{Dilipkumar N.\} and Greenbaum, \{Steven G.\} and Chapman, \{Walter G.\} and Singer, \{Philip M.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Co-published by Nanjing University and American Chemical Society.",

year = "2025",

doi = "10.1021/cbmi.4c00080",

language = "English",

journal = "Chemical and Biomedical Imaging",

issn = "2832-3637",

publisher = "American Chemical Society",

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T1 - Molecular-Level Insights into the NMR Relaxivity of Gadobutrol Using Quantum and Classical Molecular Simulations

AU - Pinheiro dos Santos, Thiago J.

AU - Fraenza, Carla C.

AU - de Araujo Lima e Souza, Giselle

AU - Pelegano-Titmuss, Emilia

AU - Asthagiri, Dilipkumar N.

AU - Greenbaum, Steven G.

AU - Chapman, Walter G.

AU - Singer, Philip M.

PY - 2025

Y1 - 2025

N2 - MRI is an indispensable diagnostic tool in modern medicine; however, understanding the molecular-level processes governing NMR relaxation of water in the presence of MRI contrast agents remains a challenge, hindering the molecular-guided development of more effective contrast agents. By using quantum-based polarizable force fields, the first-of-its-kind molecular dynamics (MD) simulations of Gadobutrol are reported where the 1H NMR longitudinal relaxivity r1 of the aqueous phase is determined without any adjustable parameters. The MD simulations of r1 dispersion (i.e., frequency dependence) show good agreement with measurements at frequencies of interest in clinical MRI. Importantly, the simulations reveal key insights into the molecular level processes leading to r1 dispersion by decomposing the NMR dipole-dipole autocorrelation function G(t) into a discrete set of molecular modes, analogous to the eigenmodes of a quantum harmonic oscillator. The molecular modes reveal important aspects of the underlying mechanisms governing r1, such as its multiexponential nature and the importance of the second eigenmodal decay. By simply analyzing the MD trajectories on a parameter-free approach, the Gadobutrol simulations show that the outer-shell water contributes ∼50% of the total relaxivity r1 compared to the inner-shell water, in contrast to simulations of (nonchelated) gadolinium-aqua where the outer shell contributes only ∼15% of r1. The deviation between simulations and measurements of r1 below clinical MRI frequencies is used to determine the low-frequency electron-spin relaxation time for Gadobutrol, in good agreement with independent studies.

AB - MRI is an indispensable diagnostic tool in modern medicine; however, understanding the molecular-level processes governing NMR relaxation of water in the presence of MRI contrast agents remains a challenge, hindering the molecular-guided development of more effective contrast agents. By using quantum-based polarizable force fields, the first-of-its-kind molecular dynamics (MD) simulations of Gadobutrol are reported where the 1H NMR longitudinal relaxivity r1 of the aqueous phase is determined without any adjustable parameters. The MD simulations of r1 dispersion (i.e., frequency dependence) show good agreement with measurements at frequencies of interest in clinical MRI. Importantly, the simulations reveal key insights into the molecular level processes leading to r1 dispersion by decomposing the NMR dipole-dipole autocorrelation function G(t) into a discrete set of molecular modes, analogous to the eigenmodes of a quantum harmonic oscillator. The molecular modes reveal important aspects of the underlying mechanisms governing r1, such as its multiexponential nature and the importance of the second eigenmodal decay. By simply analyzing the MD trajectories on a parameter-free approach, the Gadobutrol simulations show that the outer-shell water contributes ∼50% of the total relaxivity r1 compared to the inner-shell water, in contrast to simulations of (nonchelated) gadolinium-aqua where the outer shell contributes only ∼15% of r1. The deviation between simulations and measurements of r1 below clinical MRI frequencies is used to determine the low-frequency electron-spin relaxation time for Gadobutrol, in good agreement with independent studies.

KW - Gadobutrol

KW - MRI contrast agents

KW - Molecular Dynamics Simulations

KW - NMR dispersion

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DO - 10.1021/cbmi.4c00080

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JO - Chemical and Biomedical Imaging

JF - Chemical and Biomedical Imaging

ER -

Molecular-Level Insights into the NMR Relaxivity of Gadobutrol Using Quantum and Classical Molecular Simulations

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