Developing a Coarse-Grained Model for Bacterial Cell Walls and Evaluating Mechanical Properties and Free Energy Barriers

Vaiwala, Rakesh; Sharma, Pradyumn; Puranik, Mrinalini; Ayappa, K. G.

doi:10.1101/2020.03.12.985218

Cited by 5 publications

(16 citation statements)

References 58 publications

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“…In this study, the location of the two membranes was determined by using the full-length AcrAB-TolC RND pump as a guide, but the cell wall was omitted due to the lack of a CG model and paucity of details regarding the physiological location of the cell wall with respect to the protein. We note here that CG models of the E. coli cell wall have now been reported [14,15].…”

Section: Organisation Of the Cell Envelopementioning

confidence: 64%

What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

et al. 2022

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Bacterial cell envelopes are compositionally complex and crowded and while highly dynamic in some areas, their molecular motion is very limited, to the point of being almost static in others. Therefore, it is no real surprise that studying them at high resolution across a range of temporal and spatial scales requires a number of different techniques. Details at atomistic to molecular scales for up to tens of microseconds are now within range for molecular dynamics simulations. Here we review how such simulations have contributed to our current understanding of the cell envelopes of Gram-negative bacteria.

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Section: Organisation Of the Cell Envelopementioning

confidence: 64%

What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

et al. 2022

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“…To improve the efficacy and selectivity of AMPs, it is crucial to understand their interactions with different components of the bacterial cell envelope. In recent years several molecular dynamics simulations from our laboratory and others have shown that it is important to assess the barrier properties of PGN and OM which are physicochemically and mechanically distinct from the interaction with the bilayer environment of the IM [8][9][10][11][12]. Notably, the OM offers a heterogeneous barrier for antimicrobials.…”

Section: Discussionmentioning

confidence: 99%

“…With advances in force-field development and increased computing power, molecular dynamics (MD) simulations have increasingly been used to study the barrier properties of the bacterial cell envelope. Insights into the barrier properties of the bacterial membranes have recently been obtained using free energy methods based on umbrella sampling and metadynamics [8, 10, 11, 15]. The amphiphilic nature of LPS acts as a barrier for both hydrophobic and hydrophilic molecules prohibiting their translocation across the bacterial cell envelope [11].…”

Section: Introductionmentioning

confidence: 99%

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A molecular dynamics study of antimicrobial peptide translocation across the outer membrane of Gram-negative bacteria

Sharma

Ayappa

2022

Preprint

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With rising bacterial resistance, antimicrobial peptides (AMPs) have been widely investigated as potential antibacterial molecules to replace conventional antibiotics. Our understanding of the molecular mechanism for membrane disruption are largely based on AMP interactions with the inner phospholipid bilayers of both Gram-negative and Gram-positive bacteria. Mechanisms for AMP translocation across the outer membrane of Gram-negative bacteria composed of lipopolysaccharides and the asymmetric lipid bilayer are incompletely understood. In the current study, we have employed atomistic molecular dynamics and umbrella sampling simulations with an aggregate duration of ~ 8 microseconds to understand the free energy landscape of CM15 peptide within the OM of Gram-negative bacteria, E. coli. The peptide has a favourable binding free energy (-130 kJ mol-1) in the O-antigen region with a large barrier (150 kJ mol-1) at the interface between the anionic core-saccharides and upper bilayer leaflet made up of lipid A molecules. We have analyzed the peptide and membrane properties at each of the 100 ns duration umbrella sampling windows to study variations in the membrane and the peptide structure during the translocation through the OM. Interestingly the peptide is seen to elongate, adopting a membrane perpendicular orientation in the phospholipid region resulting in the formation of a transient water channel during it's translocation through the bilayer. The presence of the peptide at the lipid A and core-saccharide interface results in a 11% increase in the membrane area with the peptide adopting a predominantly membrane parallel orientation in this cation rich region. Additionally, the lateral displacement of the peptide is significantly reduced in this region, and increases toward the inner phospholipid leaflet and the outer O-antigen regions of the membrane. The peptide is found to be sufficiently hydrated across both the hydrophilic as well as hydrophobic regions of the membrane and remains unstructured without any gain in helical content. Our study unravels the complex free energy landscape for the translocation of the AMP CM15 across the outer membrane of Gram-negative bacteria and we discuss the implications of our findings with the broader question of how AMPs overcome this barrier during antimicrobial activity.

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“…13 Therefore, the glycan strands in S. aureus are modelled with a hydroxyl ('OH') group attached to the anomeric carbon of a NAM residue at the terminal ends. While, following our previous work, 29 the strands in E. coli terminate with a methoxy ('OCH 3 ') group bonded with anomeric carbon of NAM. The model glycan strands are 8 disaccharide units long.…”

Section: Single Strands Of Peptidoglycansmentioning

confidence: 99%

Differentiating interactions of antimicrobials with Gram-negative and Gram-positive bacterial cell walls using molecular dynamics simulations

Vaiwala

Sharma

Ayappa

2022

Preprint

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Developing molecular models to capture the complex physicochemical architecture of the bacterial cell wall and to study the interaction with antibacterial molecules is an important aspect of assessing and developing novel antimicrobial molecules. We carried out molecular dynamics simulations using an atomistic model of peptidoglycan (PGN) to represent the architecture for Gram-positive Staphylococcus aureus. The model is developed to capture various structural features of the staphylococcal cell wall, such as the peptide orientation, area per disaccharide, glycan length distribution, crosslinking, and pore size. A comparison of the cell wall density and electrostatic potentials is made with a previously developed cell wall model of Gram-negative bacteria, Escherichia coli, and properties for both a single and multilayered structures of the Staphylococcal cell wall are studied. We investigated the interactions of the antimicrobial peptide melittin with the PGN structures. The depth of melittin binding to PGN is more pronounced in E. coli than S. aureus, and consequently the melittin has greater contacts with glycan units of E. coli. Contacts of melittin with the amino acids of peptidoglycan are comparable across both the strains, and the D-Ala residues, which are sites for transpeptidation, show enhanced interactions with melittin. A low energetic barrier is observed for translocation thymol with the four-layered peptidoglycan model. The molecular model developed for Gram-positive PGN allows us to compare and contrast the cell wall penetrating properties with Gram-negative strains and assess for the first time binding and translocation of antimicrobial molecules for Gram-positive cell walls.

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Developing a Coarse-Grained Model for Bacterial Cell Walls and Evaluating Mechanical Properties and Free Energy Barriers

Cited by 5 publications

References 58 publications

What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

A molecular dynamics study of antimicrobial peptide translocation across the outer membrane of Gram-negative bacteria

Differentiating interactions of antimicrobials with Gram-negative and Gram-positive bacterial cell walls using molecular dynamics simulations

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