Molecular dynamics simulation of apolipoprotein E3 lipid nanodiscs

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Nanodiscs are discoidal complexes comprising a phospholipid bilayer surrounded by scaffold proteins.
• Apolipoprotein E (apoE) is crucial for lipid metabolism and transport.
• Understanding nanodisc formation and stability is key for their application in biochemistry and structural biology.

Purpose of the Study:

• To investigate the stability, size, and structure of nanodiscs formed by apolipoprotein E3 N-terminal domain (apoE3-NT) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids.
• To compare the properties of nanodiscs with parallel versus antiparallel protein configurations.
• To determine the optimal lipid-to-protein ratio for stable nanodisc formation.

Main Methods:

• Coarse-grained and all-atom molecular dynamics simulations were employed.
• Simulations explored nanodisc stability across a range of DMPC concentrations (240-420 molecules).
• Structural parameters including protein-protein interactions, lipid order, and root mean square deviation were analyzed.

Main Results:

• Stable nanodiscs were predicted for configurations containing 240 to 420 DMPC molecules.
• Antiparallel apoE3-NT configurations showed significantly higher inter-protein amino acid and ionic interactions compared to parallel configurations.
• DMPC lipid order parameters and protein backbone root mean square deviation indicated greater stability and rigidity in antiparallel arrangements.

Conclusions:

• The antiparallel configuration of apoE3-NT proteins leads to more stable and rigid nanodiscs.
• Simulation results provide insights into the structural determinants of nanodisc stability.
• This study offers a foundation for designing and utilizing nanodiscs in various biological applications.