TY - JOUR
T1 - Multiscale Simulation of Ternary Stratum Corneum Lipid Mixtures
T2 - Effects of Cholesterol Composition
AU - Shamaprasad, Parashara
AU - Moore, Timothy C.
AU - Xia, Donna
AU - Iacovella, Christopher R.
AU - Bunge, Annette L.
AU - McCabe, Clare
N1 - Funding Information:
The project was supported by Grant Number R01AR072679 from the National Institute of Arthritis and Muscoskeletal and Skin Diseases. D.X. also acknowledges support from the National Science Foundation through grant number DMR-1852157. Additional computational resources were provided by the National Energy Research Scientific Computing Center, supported by the Office of Science of the Department of Energy under Contract No. DE-AC02-05CH11231 and the Advanced Computing Center for Research and Education at Vanderbilt University.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/6/21
Y1 - 2022/6/21
N2 - Molecular dynamics simulations of mixtures of the ceramide nonhydroxy-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained force field for cholesterol was developed using the multistate iterative Boltzmann inversion (MS-IBI) method. The coarse-grained cholesterol force field is compatible with previously developed coarse-grained force fields for ceramide NS, free fatty acids, and water and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the single bilayer in water structures typically studied using molecular simulation. Cholesterol fluidizes the membrane by promoting packing defects, and an increase in cholesterol content is found to reduce the bilayer thickness due to an increase in interdigitation of the C24 lipid tails, consistent with experimental observations. Using a reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. This work highlights the importance of simulating multilayer structures, as compared to the more commonly studied bilayer systems, to enable more appropriate comparisons with multilayer experimental membranes. These results also provide validation of the efficacy of the MS-IBI derived coarse-grained force fields and the framework for multiscale simulation.
AB - Molecular dynamics simulations of mixtures of the ceramide nonhydroxy-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained force field for cholesterol was developed using the multistate iterative Boltzmann inversion (MS-IBI) method. The coarse-grained cholesterol force field is compatible with previously developed coarse-grained force fields for ceramide NS, free fatty acids, and water and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the single bilayer in water structures typically studied using molecular simulation. Cholesterol fluidizes the membrane by promoting packing defects, and an increase in cholesterol content is found to reduce the bilayer thickness due to an increase in interdigitation of the C24 lipid tails, consistent with experimental observations. Using a reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. This work highlights the importance of simulating multilayer structures, as compared to the more commonly studied bilayer systems, to enable more appropriate comparisons with multilayer experimental membranes. These results also provide validation of the efficacy of the MS-IBI derived coarse-grained force fields and the framework for multiscale simulation.
UR - http://www.scopus.com/inward/record.url?scp=85132453796&partnerID=8YFLogxK
U2 - 10.1021/acs.langmuir.2c00471
DO - 10.1021/acs.langmuir.2c00471
M3 - Article
C2 - 35671175
AN - SCOPUS:85132453796
SN - 0743-7463
VL - 38
SP - 7496
EP - 7511
JO - Langmuir
JF - Langmuir
IS - 24
ER -