OMSys: Towards a systems model of a bacterial outer membrane
Lead Research Organisation:
University of Oxford
Department Name: Biochemistry
Abstract
Many bacteria have an outer membrane which is the interface between the cell and its environment. The components of this membrane are well studied at an individual level, but there is a need to model and understand the outer membrane as a whole. In this project we aim to develop such a model of a bacterial outer membrane, linking computer simulations of the component molecules through to a more 'systems biology' approach to modelling the outer membrane as a whole. Such an approach to modelling an OM must be multi-scale i.e. it must embrace a number of levels ranging from atomistic level modelling of e.g. the component proteins through to higher level 'agent-based' modelling of the interplay of multiple components within the outer membrane as a whole. The different levels of description will be integrated to enable predictive modelling in order to explore the roles of outer membrane changes in e.g. antibiotic resistance.
Technical Summary
In this project we aim to develop a model of a bacterial outer membrane (OM), linking biomolecular simulations through to computational systems biology approaches. Such an approach to modelling an OM must be multi-scale i.e. it must embrace a number of levels: (i) atomistic level modelling of protein/ligand interactions; (ii) coarse-grained modelling of both outer membrane proteins and lipoproteins and of their lipopolysaccharide/phospholipid/peptidoglycan environment; and (iii) higher level e.g. agent-based modelling of the interplay of multiple components within the OM as a whole. The different levels of description will be integrated to enable predictive modelling of bacterial OMs in order to explore the roles of OM changes in e.g. antibiotic resistance and envelope stress responses.
Organisations
Publications
Abad E
(2009)
On a novel rate theory for transport in narrow ion channels and its application to the study of flux optimization via geometric effects.
in The Journal of chemical physics
Andres-Enguix I
(2012)
Functional analysis of missense variants in the TRESK (KCNK18) K channel.
in Scientific reports
Aryal P
(2014)
A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel.
in Nature communications
Aryal P
(2015)
Hydrophobic gating in ion channels.
in Journal of molecular biology
Balali-Mood K
(2009)
Interaction of monotopic membrane enzymes with a lipid bilayer: a coarse-grained MD simulation study.
in Biochemistry
Bavro VN
(2012)
Structure of a KirBac potassium channel with an open bundle crossing indicates a mechanism of channel gating.
in Nature structural & molecular biology
Berks BC
(2014)
Structural biology of Tat protein transport.
in Current opinion in structural biology
Bollepalli MK
(2014)
State-dependent network connectivity determines gating in a K+ channel.
in Structure (London, England : 1993)
Chavent M
(2014)
Methodologies for the analysis of instantaneous lipid diffusion in MD simulations of large membrane systems.
in Faraday discussions
Chetwynd A
(2010)
The energetics of transmembrane helix insertion into a lipid bilayer.
in Biophysical journal
| Description | We developed methods which allowed us to show massively hindered diffusion of bacterial outer membrane proteins |
| Exploitation Route | collaboration initiated with experimental colleagues |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | I have initiated collaborative discussions with a number of pharmaceutical companies (UCB, NovoNordisk, Novartis, Ipsen) interested in large scale membrane simulations using methods which we started to develop during this project. |
| First Year Of Impact | 2015 |
| Sector | Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |