Optimization of CHARMM force field parameters for ryanodine receptor inhibitory drug dantrolene using FFTK and FFParam

Saliha Nur Uludağ; Cemil Can Saylan; Adem Tekin; Sefer Baday

doi:10.1007/s00894-024-05841-3

Optimization of CHARMM force field parameters for ryanodine receptor inhibitory drug dantrolene using FFTK and FFParam

Saliha Nur Uludağ, Cemil Can Saylan, Adem Tekin, Sefer Baday^*

^*Corresponding author for this work

Informatics Institute

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Context: Ryanodine receptors (RyRs) are large intracellular ligand-gated calcium release ion channels. Mutations in human RyR1 in combination with a volatile anesthetic or muscle relaxant are known to cause leaky RyRs resulting in malignant hyperthermia (MH). This has long been primarily treated with the RyR inhibitory drug dantrolene. Alternatives to dantrolene as a RyR inhibitor may be found through computer-aided drug design. Additionally, molecular dynamics (MD) studies of dantrolene interacting with RyRs may reveal its full mechanism of action. The availability of accurate force field parameters is important for the success of both. Methods: In this study, force field parameters for dantrolene were obtained from the CHARMM General Force Field (CGenFF) program and optimized using the force field toolkit (FFTK) and FFParam programs. The obtained parameters were then validated by a comparison between calculated and experimental IR spectra and normal mode analysis, among other techniques.

Original language	English
Article number	46
Journal	Journal of Molecular Modeling
Volume	30
Issue number	2
DOIs	https://doi.org/10.1007/s00894-024-05841-3
Publication status	Published - Feb 2024

Bibliographical note

Publisher Copyright:
© 2024, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Funding

This work was supported by the Turkish-Slovak Joint Partnership of The Scientific and Technological Research Council of Turkey (TUBITAK) [Grant Agreement Number:119Z578]. Computing resources used in this work were provided by the National Center for High Performance Computing of Turkey (UHeM) under grant number 5009062021.

Funders	Funder number
National Center for High Performance Computing of Turkey
Turkish-Slovak Joint Partnership of The Scientific and Technological Research Council of Turkey
Ulusal Yüksek Başarımlı Hesaplama Merkezi, Istanbul Teknik Üniversitesi	5009062021
Türkiye Bilimsel ve Teknolojik Araştırma Kurumu	:119Z578

Keywords

Dantrolene
FFParam
FFTK
Force field
Ryanodine receptor

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10.1007/s00894-024-05841-3

Cite this

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abstract = "Context: Ryanodine receptors (RyRs) are large intracellular ligand-gated calcium release ion channels. Mutations in human RyR1 in combination with a volatile anesthetic or muscle relaxant are known to cause leaky RyRs resulting in malignant hyperthermia (MH). This has long been primarily treated with the RyR inhibitory drug dantrolene. Alternatives to dantrolene as a RyR inhibitor may be found through computer-aided drug design. Additionally, molecular dynamics (MD) studies of dantrolene interacting with RyRs may reveal its full mechanism of action. The availability of accurate force field parameters is important for the success of both. Methods: In this study, force field parameters for dantrolene were obtained from the CHARMM General Force Field (CGenFF) program and optimized using the force field toolkit (FFTK) and FFParam programs. The obtained parameters were then validated by a comparison between calculated and experimental IR spectra and normal mode analysis, among other techniques.",

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doi = "10.1007/s00894-024-05841-3",

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AU - Uludağ, Saliha Nur

AU - Saylan, Cemil Can

AU - Tekin, Adem

AU - Baday, Sefer

PY - 2024/2

Y1 - 2024/2

N2 - Context: Ryanodine receptors (RyRs) are large intracellular ligand-gated calcium release ion channels. Mutations in human RyR1 in combination with a volatile anesthetic or muscle relaxant are known to cause leaky RyRs resulting in malignant hyperthermia (MH). This has long been primarily treated with the RyR inhibitory drug dantrolene. Alternatives to dantrolene as a RyR inhibitor may be found through computer-aided drug design. Additionally, molecular dynamics (MD) studies of dantrolene interacting with RyRs may reveal its full mechanism of action. The availability of accurate force field parameters is important for the success of both. Methods: In this study, force field parameters for dantrolene were obtained from the CHARMM General Force Field (CGenFF) program and optimized using the force field toolkit (FFTK) and FFParam programs. The obtained parameters were then validated by a comparison between calculated and experimental IR spectra and normal mode analysis, among other techniques.

AB - Context: Ryanodine receptors (RyRs) are large intracellular ligand-gated calcium release ion channels. Mutations in human RyR1 in combination with a volatile anesthetic or muscle relaxant are known to cause leaky RyRs resulting in malignant hyperthermia (MH). This has long been primarily treated with the RyR inhibitory drug dantrolene. Alternatives to dantrolene as a RyR inhibitor may be found through computer-aided drug design. Additionally, molecular dynamics (MD) studies of dantrolene interacting with RyRs may reveal its full mechanism of action. The availability of accurate force field parameters is important for the success of both. Methods: In this study, force field parameters for dantrolene were obtained from the CHARMM General Force Field (CGenFF) program and optimized using the force field toolkit (FFTK) and FFParam programs. The obtained parameters were then validated by a comparison between calculated and experimental IR spectra and normal mode analysis, among other techniques.

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KW - FFParam

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Optimization of CHARMM force field parameters for ryanodine receptor inhibitory drug dantrolene using FFTK and FFParam

Abstract

Bibliographical note

Funding

Keywords

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