Figure out ideal membranes for study: mix of phospholipids etc.

[jarvist]

2012 Cahill: "Of the four main phospholipids in membranes, threephosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM)—are neutral, and one, phosphatidylserine (PS), is negatively charged. In a living cell, PE and PS are mostly in the cytosolic layer of the plasma membrane; PC and SM are mostly in the outer layer [1]; and the electrostatic potential of the cytosol is 20 to 120 mV lower than that of the extracellular environment."

[jarvist]

Top of my head things to consider about the type of membrane :-

• gram negative vs. gram positive; should we just ignore gram negatives with their funky cell wall, or include the external membrane of the gram negative family only
• I think red blood cells are the standard for AMP assays? Or is there a more representative Mammalian type membrane? (Cahill refers to Liver cells.)
• Extension to cancer - I think I read somewhere that cancer cells are often missing cholesterol, and have a lot of the PC/SM phospholipids (?)

[jarvist]

More practical / technical things to consider :-

• How to build these. Within the Martini worldinsane seemed to work quite easily; but there's a next gen python code
• How big a system to simulate?
• For the Cahill work - what's the best way to simulate these as seminfinite layers, so that we can sample the dielectric function.

[KamDB]

https://doi.org/10.1016/j.bcp.2022.115296

[KamDB]

The phospholipid membrane compositions of bacterial cells, cancer cell lines and biological samples from cancer patients
Experimentally derived membrane compositions! May have to do a few general bacterial membrane models with differing lipid compositions.

https://doi.org/10.1039/D1SC03597E

In general, the outer phospholipid membrane of bacterial cells contains mixtures of polar phospholipids such as PE and PG.54–56 Therefore, traditionally these bacterial phospholipid membranes have been modelled in synthetic systems using a mixture of PE : PG in a 3 : 1 ratio.55,57 However, as detailed in Table 3, this is not representative of many naturally derived bacterial membranes. For example, although Gram-negative E. coli has a bacterial phospholipid composition that is very similar to these conventional model systems (PE : PG : CL 75 : 20 : 5),57 this is not the case for Gram-positive methicillinsensitive S. aureus U-71 (PG : L-PG : CL 80 : 12 : 5).58

As exemplified in Table 3, the phospholipid composition of AMR bacteria differs significantly from those membranes studied from analogous non-resistant bacterial strains. For example, the clinical pair of daptomycin susceptible (S447) and daptomycin resistant (R446) strains of Enterococcus faecium66 have a phospholipid composition PG : L-PG : CL : DAG 34 : 14 : 29 : 13 and PG : L-PG : CL : DAG 15 : 16 : 47 : 23 respectively.66 This was interesting, as there are a number of unique bacterial lipids that are already associated with antimicrobial resistance including lipid A and teichoic acids.79
Therefore, when considering the design and delivery of novel therapeutics to treat AMR infections where interaction with, or permeation through the cell membrane is critical, the differences in phospholipid membrane composition should also be taken into consideration.

[jarvist]

Really useful figures! Could you add references from where they came from @KamDB ?

[KamDB]

Elastic moduli of normal and cancer cell membranes revealed by molecular dynamics simulations
https://doi.org/10.1039/D1CP04836H
Really nice paper in terms of physical properties of cell membranes

Normal cell membranes have a highly asymmetric lipid composition.6 That is, the extracellular leaflet is mainly composed of phosphatitylcholine (PC) and sphingo lipids, and the intracellular leaflet is mostly composed of phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Is is known that the concentration of the negatively charged PS lipids is increased by 5–9 times in the outer leaflet when normal membranes are transformed to cancer membranes, and this is usually considered as a biological cue that is related to the apoptotic pathway.7,8 As a consequence, cancer membranes have a less negative membrane potential than those of normal membranes.9–11 Another alteration in cancer cells is a reduction in the cholesterol concentration in their membranes,12 which results in decreases of the order of lipid hydrocarbon chains and membrane thickness, and an increase in the surface area of lipids.13–17

As seen, the asymmetry of lipid distributions between two leaflets, which is a general feature of normal membranes, is taken into accountin the construction. Having designed the normal membranes, the cancer counterparts are obtained by symmetrizing the number of lipids between the two leaflets. This mimics the overexpression in PS/PE in the outer leaflets of cancer membranes. The population of cholesterol is kept the same between the two leaflets.

Each model contains four lipid types: 1,2-dioleoylsn-glycero-3-phosphocholine (DOPC), sphingomyelin (SM) lipids, dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) lipids. Following the work of Rivel et al., we add 33% cholesterol (CHL) to each membrane model. This concentration is about the typical sterol concentration in the mammalian plasma membrane.44 We also construct a model (M5) containing only 15% cholestrol, but where the numbers of lipids are the same as that of the M1 model. These two models M1 and M5 enable us to study the effect of the reduction in cholesterol concentration.

Interesting note :
Our normal cell model M4 is constructed using the same mole fractions of lipids as the realistic mammalian cell membrane models developed by Ingolfsson et al.26 The cancer cell counterpart M4- is obtained via symmetrization of the distribution of lipids between the two leaflets of M4 [Table 2]. The models of Ingolfsson et al. are very complex, consisting of different lipid species, combining different types of head group and different types of tail asymmetrically distributed across the two leaflets. However, their MD simulations using the coarse grained MARTINI force field show striking similarities in the overall bilayer properties, such as the bilayer thickness, lipid tail order, diffusion, flip-flop, and average neighbours, despite the significant difference in lipid compositions between the two models. Our all-atom simulations show that the structural properties of M4 and M4- are quite similar. These results may suggest that use of the coarse-grained MARTINI or all-atom CHARMM36 force field should not yield significant differences in the overall bilayer structural properties.

Referring to this paper - https://doi.org/10.1016%2Fj.bpj.2017.10.017 - the author previously came out with a martini model - https://doi.org/10.1021/ja507832e - where they simulated a 'normal' human membrane using 60+ lipids

[KamDB]

Computational Design of Pore-Forming Peptides with Potent Antimicrobial and Anticancer Activities
https://doi.org/10.1021/acs.jmedchem.4c00912

Interesting note for pH sensitivity of cancer cells:
Cancer cells are also surrounded by an acidic extracellular microenvironment,83,84 due to lactate secretion from anaerobic glycolysis. This acidic microenvironment could be exploited to increase the net charge of the peptides at low pH and enhance peptide selectivity for cancer cells.25,26 This approach could be applied to both solid tumors and blood cancers, as the microenvironment of lymph nodes, the main site of cell proliferation in leukemia and lymphoma (e.g.,chronic lymphocytic leukemia), is acidic.85 In this context, the Histidine residue has been shown to be beneficial,86−89 because it changes protonation state at around pH 6 (pKa ∼ 6), i.e., it carries a +1 e charge at pH <6, is partially charged at pH ∼ 6, and is mostly neutral at pH >6 .42,43 We rationally designed a H-variant peptide, LP40, by replacing the Ks at the peptide ends with Hs while leaving the Ks in the mid sequence intact to preserve the TBP-stabilizing K-D salt bridges.