Molecular Dynamics Simulation of Apolipoprotein E3 Lipid Nanodiscs

TL;DR

This study uses molecular dynamics simulations to analyze the stability, structure, and interactions of apolipoprotein E3-based nanodiscs with varying lipid content and protein configurations, revealing antiparallel arrangements are more stable.

Contribution

It provides detailed computational insights into nanodisc stability and structure, highlighting the differences between parallel and antiparallel protein configurations.

Findings

Antiparallel configurations show more amino acid interactions and ionic contacts.

Nanodiscs with 240-420 DMPC molecules are stable.

Antiparallel nanodiscs are more stable and rigid than parallel ones.

Abstract

Nanodiscs are binary discoidal complexes of a phospholipid bilayer circumscribed by belt-like helical scaffold proteins. Using coarse-grained and all-atom molecular dynamics simulations, we explore the stability, size, and structure of nanodiscs formed between the N-terminal domain of apolipoprotein E3 (apoE3-NT) and variable number of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) molecules. We study both parallel and antiparallel double-belt configurations, consisting of four proteins per nanodisc. Our simulations predict nanodiscs containing between 240 and 420 DMPC molecules to be stable. The antiparallel configurations exhibit an average of 1.6 times more amino acid interactions between protein chains and 2 times more ionic contacts, compared to the parallel configuration. With one exception, DMPC order parameters are consistently larger in the antiparallel configuration than in the parallel one. In most cases, the root mean square deviation of the positions of the protein backbone atoms is smaller in the antiparallel configuration. We further report nanodisc size, thickness, radius of gyration, and solvent accessible surface area. Combining all investigated parameters, we hypothesize the antiparallel protein configuration leading to more stable and more rigid nanodiscs than the parallel one.