A method for construction and optimization of lipid nanodisks for molecular dynamics simulations

Ivanuš, Bor (author), Rems, Lea (mentor), Tarek, Mounir (comentor)

Lipid nanodisks are lipid bilayer structures stabilized by a belt of alipoproteins. They play a critical role in studying membrane proteins and developing drug delivery systems. Mimetic peptides offer a simplified yet effective alternative to full-length apolipoproteins in stabilizing these nanodisks, providing a platform for understanding lipid-protein interactions and exploring therapeutic applications. The objective of this thesis was to develop, implement, and test a computational protocol for constructing and simulating nanodisks composed of lipid bilayers and stabilized by mimetic peptides, using molecular dynamics all-atom simula tions with the charmm36m forcefield. Five all-atom simulations were conducted to study the structural dynamics of nanodisks formed by 14A peptide dimers and DMPClipids. Anadditional simulation was done by replacing DMPC with POPC and cholesterol, to study the effect of different lipids on nanodisk properties. The presence of cholesterol in the POPC system led to slower stabilization and less shrinkage, likely due to increased membrane rigidity. Coarse-grained simulations using the Martini 3 forcefield were explored for their potential to accelerate sim ulation times. Construction was successful, but the coarse-grain models failed to maintain structural integrity during production runs, indicating that current coarse-grain models may not accurately represent interactions between peptide dimers. While coarse-grain simulations offer the potential for significant accelera tion of the simulation speed, further refinement of the forcefield and stabilization strategies are necessary for reliable nanodisk modeling.

• Language: English
• Keywords: nanodisks, mimetic peptides, molecular dynamics simulations, all atom, coarse-grain, lipid bilayer, Lipid-protein interactions, apolipoproteins
• Work type: Master's thesis/paper
• Organization: FE - Faculty of Electrical Engineering
• Year: 2024
• PID: 20.500.12556/RUL-164786
• Publication date in RUL: 12.11.2024

Secondary language

• Language: Slovenian
• Title: Metoda za konstrukcijo in optimizacijo lipidnih nanodiskov za simulacije molekularne dinamike

Abstract

Lipoproteini so nanostrukture, bistvene za transport lipidov v krvnem obtoku zaradi hidrofobnosti lipidov. Sestavljeni so iz apolipoproteinov in razliˇ cnih lipi dov, vkljuˇcno s holesterolom in trigliceridi. Med ˇstirimi glavnimi vrstami lipopro teinov—HDL, LDL, VLDL in IDL—je HDL najbolj znan po svoji sestavi in funkciji [1]. HDL, ki je sestavljen predvsem apolipoproteina A1 (Apo-AI) in fosfolipidov, je kljuˇcen za reverzni transport holesterola (angl. reverse cholesterol transport), kar zmanjˇsuje aterosklerozo in tveganje za kardiovaskularne bolezni.

• Keywords: nanodiski, mimetiˇcni peptidi, simulacije molekularne di namike, atomistiˇcno polje sil, grobozrnato polje sil, lipidni dvosloj, interakcije lipid-protein, apolipoproteini