TY - JOUR
T1 - The effect of high pressure on the NMDA receptor
T2 - molecular dynamics simulations
AU - Bliznyuk, Alice
AU - Grossman, Yoram
AU - Moskovitz, Yevgeny
N1 - Funding Information:
The Oak Ridge Leadership Computational Facility (OLCF) at Oak Ridge National Laboratory provided access to the Titan supercomputer. The authors wish to thank Mr. Bogdan Iaparov for calculating the DOPC order parameters, Veronika Bikova and Anastasia Bazhutina for molecular volume and RDF calculations. Y.M. was partly supported by UrFU Competitiveness Enhancement Program (agreement 02.A03.21.0006).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Professional divers exposed to ambient pressures above 11 bar develop the high pressure neurological syndrome (HPNS), manifesting as central nervous system (CNS) hyperexcitability, motor disturbances, sensory impairment, and cognitive deficits. The glutamate-type N-methyl-D-aspartate receptor (NMDAR) has been implicated in the CNS hyperexcitability of HPNS. NMDARs containing different subunits exhibited varying degrees of increased/decreased current at high pressure. The mechanisms underlying this phenomenon remain unclear. We performed 100 ns molecular dynamics (MD) simulations of the NMDAR structure embedded in a dioleoylphosphatidylcholine (DOPC) lipid bilayer solvated in water at 1 bar, hydrostatic 25 bar, and in helium at 25 bar. MD simulations showed that in contrast to hydrostatic pressure, high pressure helium causes substantial distortion of the DOPC membrane due to its accumulation between the two monolayers: reduction of the Sn-1 and Sn-2 DOPC chains and helium-dependent dehydration of the NMDAR pore. Further analysis of important regions of the NMDAR protein such as pore surface (M2 α-helix), Mg2+ binding site, and TMD-M4 α-helix revealed significant effects of helium. In contrast with previous models, these and our earlier results suggest that high pressure helium, not hydrostatic pressure per se, alters the receptor tertiary structure via protein-lipid interactions. Helium in divers’ breathing mixtures may partially contribute to HPNS symptoms.
AB - Professional divers exposed to ambient pressures above 11 bar develop the high pressure neurological syndrome (HPNS), manifesting as central nervous system (CNS) hyperexcitability, motor disturbances, sensory impairment, and cognitive deficits. The glutamate-type N-methyl-D-aspartate receptor (NMDAR) has been implicated in the CNS hyperexcitability of HPNS. NMDARs containing different subunits exhibited varying degrees of increased/decreased current at high pressure. The mechanisms underlying this phenomenon remain unclear. We performed 100 ns molecular dynamics (MD) simulations of the NMDAR structure embedded in a dioleoylphosphatidylcholine (DOPC) lipid bilayer solvated in water at 1 bar, hydrostatic 25 bar, and in helium at 25 bar. MD simulations showed that in contrast to hydrostatic pressure, high pressure helium causes substantial distortion of the DOPC membrane due to its accumulation between the two monolayers: reduction of the Sn-1 and Sn-2 DOPC chains and helium-dependent dehydration of the NMDAR pore. Further analysis of important regions of the NMDAR protein such as pore surface (M2 α-helix), Mg2+ binding site, and TMD-M4 α-helix revealed significant effects of helium. In contrast with previous models, these and our earlier results suggest that high pressure helium, not hydrostatic pressure per se, alters the receptor tertiary structure via protein-lipid interactions. Helium in divers’ breathing mixtures may partially contribute to HPNS symptoms.
UR - http://www.scopus.com/inward/record.url?scp=85070578941&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-47102-x
DO - 10.1038/s41598-019-47102-x
M3 - Article
C2 - 31346207
AN - SCOPUS:85070578941
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 10814
ER -