All-Atom Modeling of Complex Cellular Membranes

Abstract

Cell membranes are composed of a variety of lipids and proteins where they interact with each other to fulfill their roles. The first step in modeling these interactions in molecular simulations is to have reliable mimetics of the membrane’s lipid environment. This Feature Article presents our recent efforts to model complex cellular membranes using all-atom force fields. A short review of the CHARMM36 (C36) lipid force field and its recent update to incorporate the long-range dispersion is presented. Key examples of model membranes mimicking various species and organelles are given. These include single-celled organisms such as bacteria (E. coli., chlamydia, and P. aeruginosa) and yeast (plasma membrane, endoplasmic reticulum, and trans-Golgi network) and more advanced ones such as plants (soybean and Arabidopsis thaliana) and mammals (ocular lens, stratum corneum, and peripheral nerve myelin). Leaflet asymmetry in composition has also been applied to some of these models. With the increased lipid diversity in the C36 lipid FF, these complex models can better reflect the structural, mechanical, and dynamic properties of realistic membranes and open an opportunity to study biological processes involving other molecules.

Generation and Computational Characterization of a Complex Staphylococcus aureus Lipid Bilayer

“…Models with diverse types of headgroups and fatty acyl tails can provide more realistic biophysical and biochemical properties, − and the work here falls within correspondingly more complex molecular models that have been constructed for other kinds of bacteria or cells . For example, 5 different phospholipids and cholesterol molecules were initially used to model a yeastlike membrane .…”

Current Trends and Changes in Use of Membrane Molecular Dynamics Simulations within Academia and the Pharmaceutical Industry

“…Invariably there is a need for large scale membrane components, as the number of different membranes in a single cell include nuclear, golgi, phagosomes, proteasomes, lysosomes, excretory vesicles and a number of specialized elements for specific cell types. Some of these have already begun to be simulated, apparent from reviews of complex membrane systems, now including a number of intercellular membranes and bacterial cell membranes [ 180 , 181 , 182 ]. Additionally, each of these has localized membrane differences, such as lipid rafts and charge, or drastic pH and other solvent extremes on either side.…”

Two decades of Martini: Better beads, broader scope

“…However, the hope that, with a continuing increase in capacity, all processes could be captured with such detailed models turned out to be idle. Even today, with access to exascale computing power, all‐atom simulations are still limited to spatiotemporal scales less than 100 nm and typically covering few microseconds 3–5 . Considering the gap with processes in real life, the need for a CG description is still as urgent as in the early days 5–11 .…”

“…Even today, with access to exascale computing power, all-atom simulations are still limited to spatiotemporal scales less than 100 nm and typically covering few microseconds. [3][4][5] Considering the gap with processes in real life, the need for a CG description is still as urgent as in the early days. [5][6][7][8][9][10][11] The requirement of more sampling speed became (re)apparent in the late 90s, and caused a surge in the development of numerous enhanced sampling methods as well as the re-valuation of the principle of coarsegraining.…”