Comparative molecular dynamics simulation studies of realistic eukaryotic, prokaryotic, and archaeal membranes

Kong, Lingyang; Hartnagel, Tim J.; Carpino, Carly A.; Gee, Stephen E.; Picarello, Danielle M; Rubin, A.; Lee, Jumin; Park, Soo Hyung; Pogozheva, Irina D.; Lomize, Andrei L.; Im, Wonpil

doi:10.1016/j.bpj.2021.11.2361

Cited by 1 publication

(1 citation statement)

References 32 publications

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“…The initial conformation of sphingomyelin was manually placed along the hydrophobic groove of hSMPD2 and the RosettaLigand docking protocol 51 was used for molecular docking with a library of 300 conformations of sphingomyelin selected from CHARMM-GUI archive for biomembrane systems 52 .…”

Section: Molecular Docking Of Sphingomyelin Along the Hydrophobic Gro...mentioning

confidence: 99%

Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)

Yi,

Qi,

Yin

et al. 2023

Nat Commun

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Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full-length structure of human neutral SMase has not been resolved; therefore, its catalytic mechanism remains unknown. Here, we resolve the structure of human full-length neutral SMase, sphingomyelinase 1 (SMPD2), which reveals that C-terminal transmembrane helices contribute to dimeric architecture of hSMPD2 and that D111 − K116 loop domain is essential for substrate hydrolysis. Coupled with molecular docking, we clarify the binding pose of sphingomyelin, and site-directed mutagenesis further confirms key residues responsible for sphingomyelin binding. Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamic (MD) simulations are utilized to elaborate the catalysis of hSMPD2 with the reported in vitro substrates, sphingomyelin and lyso-platelet activating fator (lyso-PAF). Our study provides mechanistic details that enhance our knowledge of lipid metabolism and may lead to an improved understanding of ceramide in disease and in cancer treatment.

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Section: Molecular Docking Of Sphingomyelin Along the Hydrophobic Gro...mentioning

confidence: 99%

Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)

Yi,

Qi,

Yin

et al. 2023

Nat Commun

View full text Add to dashboard Cite

show abstract

Comparative molecular dynamics simulation studies of realistic eukaryotic, prokaryotic, and archaeal membranes

Cited by 1 publication

References 32 publications

Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)

Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)

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