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Atomistic and coarse grain simulations of the cell envelope of Gram-negative bacteria: what have we learned?

Atomistic and coarse grain simulations of the cell envelope of Gram-negative bacteria: what have we learned?
Atomistic and coarse grain simulations of the cell envelope of Gram-negative bacteria: what have we learned?
Bacterial membranes, and those of Gram-negative bacteria in particular, are some of the most biochemically diverse membranes known. They incorporate a wide range of lipid types and proteins of varying sizes, architectures, and functions. While simpler biological membranes have been the focus of myriad simulation studies over the years that have yielded invaluable details to complement, and often to direct, ongoing experimental studies, simulations of complex bacterial membranes have been slower to emerge. However, the past few years have seen tremendous activity in this area, leading to advances such as the development of atomistic and coarse-grain models of the lipopolysaccharide (LPS) component of the outer membrane that are compatible with widely used simulation codes. In this Account, we review our contributions to the field of molecular simulations of the bacterial cell envelope, including the development of models of both membranes and the cell wall of Gram-negative bacteria, with a predominant focus on E. coli. At the atomistic level, simulations of chemically accurate models of both membranes have revealed the tightly cross-linked nature of the LPS headgroups and have shown that penetration of solutes through these regions is not as straightforward as the route through phospholipids. The energetic differences between the two routes have been calculated. Simulations of native outer membrane proteins in LPS-containing membranes have shown that the conformational dynamics of the proteins is not only slower in LPS but also different compared to in simpler models of phospholipid bilayers. These chemically more complex and consequently biologically more relevant models are leading to details of conformational dynamics that were previously inaccessible from simulations. Coarse-grain models have enabled simulations of multiprotein systems on time scales of microseconds, leading to insights not only into the rates of protein and lipid diffusion but also into the trends in their respective directions of flow. We find that the motions of LPS molecules are highly correlated with each other but also with outer membrane proteins embedded within the membrane. We have shown that the two leaflets of the outer membrane exhibit communication, whereby regions of low disorder in one leaflet correspond to regions of high disorder in the other. The cell wall remains a comparatively neglected component, although models of the E. coli peptidoglycan are now emerging, particularly at the atomistic level. Our simulations of Braun's lipoprotein have shown that bending and tilting of this protein afford a degree of variability in the gap between the cell wall and the OM. The noncovalent interactions with the cell wall of proteins such as OmpA can further influence the width of this gap by extension or contraction of their linker domains. Overall we have shown that the dynamics of proteins, lipids, and other molecular species within the outer membrane cannot be approximated using simpler phospholipid bilayers, if one is addressing questions regarding the in vivo behavior of Gram-negative bacteria. These membranes have their own unique chemical characteristics that cannot be decoupled from their biological functions.
0001-4842
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Piggot, Thomas
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Piggot, Thomas
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9

Khalid, Syma, Piggot, Thomas and Samsudin, Firdaus (2018) Atomistic and coarse grain simulations of the cell envelope of Gram-negative bacteria: what have we learned? Accounts of Chemical Research. (doi:10.1021/acs.accounts.8b00377).

Record type: Article

Abstract

Bacterial membranes, and those of Gram-negative bacteria in particular, are some of the most biochemically diverse membranes known. They incorporate a wide range of lipid types and proteins of varying sizes, architectures, and functions. While simpler biological membranes have been the focus of myriad simulation studies over the years that have yielded invaluable details to complement, and often to direct, ongoing experimental studies, simulations of complex bacterial membranes have been slower to emerge. However, the past few years have seen tremendous activity in this area, leading to advances such as the development of atomistic and coarse-grain models of the lipopolysaccharide (LPS) component of the outer membrane that are compatible with widely used simulation codes. In this Account, we review our contributions to the field of molecular simulations of the bacterial cell envelope, including the development of models of both membranes and the cell wall of Gram-negative bacteria, with a predominant focus on E. coli. At the atomistic level, simulations of chemically accurate models of both membranes have revealed the tightly cross-linked nature of the LPS headgroups and have shown that penetration of solutes through these regions is not as straightforward as the route through phospholipids. The energetic differences between the two routes have been calculated. Simulations of native outer membrane proteins in LPS-containing membranes have shown that the conformational dynamics of the proteins is not only slower in LPS but also different compared to in simpler models of phospholipid bilayers. These chemically more complex and consequently biologically more relevant models are leading to details of conformational dynamics that were previously inaccessible from simulations. Coarse-grain models have enabled simulations of multiprotein systems on time scales of microseconds, leading to insights not only into the rates of protein and lipid diffusion but also into the trends in their respective directions of flow. We find that the motions of LPS molecules are highly correlated with each other but also with outer membrane proteins embedded within the membrane. We have shown that the two leaflets of the outer membrane exhibit communication, whereby regions of low disorder in one leaflet correspond to regions of high disorder in the other. The cell wall remains a comparatively neglected component, although models of the E. coli peptidoglycan are now emerging, particularly at the atomistic level. Our simulations of Braun's lipoprotein have shown that bending and tilting of this protein afford a degree of variability in the gap between the cell wall and the OM. The noncovalent interactions with the cell wall of proteins such as OmpA can further influence the width of this gap by extension or contraction of their linker domains. Overall we have shown that the dynamics of proteins, lipids, and other molecular species within the outer membrane cannot be approximated using simpler phospholipid bilayers, if one is addressing questions regarding the in vivo behavior of Gram-negative bacteria. These membranes have their own unique chemical characteristics that cannot be decoupled from their biological functions.

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ACC_CHEM_RES_SK_10102018_nh - Accepted Manuscript
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Accepted/In Press date: 18 December 2018
e-pub ahead of print date: 18 December 2018

Identifiers

Local EPrints ID: 427197
URI: http://eprints.soton.ac.uk/id/eprint/427197
ISSN: 0001-4842
PURE UUID: f999be57-a8d2-4c9b-a68c-a7633cb21478
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044
ORCID for Firdaus Samsudin: ORCID iD orcid.org/0000-0003-2766-4459

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Date deposited: 07 Jan 2019 17:30
Last modified: 26 Nov 2021 07:10

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Contributors

Author: Syma Khalid ORCID iD
Author: Thomas Piggot
Author: Firdaus Samsudin ORCID iD

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