Towards a Virtual Bacterial Cell Envelope

Jul 15, 2024

Seminar Presentation Notes: Towards a Virtual Bacterial Cell Envelope

Introduction

  • Speaker: Professor Simon Khalid
  • Title: Towards a Virtual Bacterial Cell Envelope: Adding Biological Complexity to Biomolecular MD Simulations

Background and Speaker Introduction

  • Introduced by: Sarah and Pete
  • Speaker's Background: PhD with Mark Roger, postdoc in Mark Samson's lab
  • Key Interests: Bacterial membranes, simulations of bacterial envelopes
  • Connection with Pete: Long-term collaboration, co-supervising PhD students

Outline

  1. Introduction to HEC Biosim
  2. Overview of Research on Bacterial Cell Envelopes
  3. Detailed Simulations and Discoveries
  4. Future Directions

HEC Biosim

Overview

  • UK-wide consortium supporting biomolecular simulation community
  • Provides access to high-end computing resources (e.g., Archer, Tier 2 machines)
  • Offers expertise, benchmarking, and technical support

Resources and Support

  • Applications for computing time on Archer and Jade (GPU cluster)
  • Online forms for applying for computational resources
  • Expertise in different molecular dynamics codes

Management Committee

  • Composed of experts from various UK universities
  • Represents different application types (capability-based vs. capacity-based)
  • James Gabby Rayette: Core support from STFC

UK HPC Landscape

  • Archer upgrading to Archer 2
  • Introduction of Tier 2 machines
  • Levels of computing resources: Tier 3 (local), Tier 2 (intermediate), Tier 1 (national), Tier 0 (international)

Access and Collaboration

  • Primarily open to UK universities, but international access through schemes like PRACE (Europe) and INCITE (USA)

Research on Bacterial Cell Envelopes

E. coli Cell Envelope Structure

  • Outer Membrane: Complex, asymmetric, LPS (lipopolysaccharide)
  • Inner Membrane: Symmetric, phospholipids
  • Periplasm: Aqueous, contains peptidoglycan (cell wall)

Motivations for Simulations

  • Understand and rationalize experimental observations at molecular level
  • Study conditions difficult to achieve experimentally
  • Propose new hypotheses
  • Drive experimental work

LPS Models

  • Existing models: Amber (inaccurate tails), newer models by Gromos and Charm
  • Importance of cations (calcium and magnesium) in membrane integrity

OMPhE and Peptidoglycan Binding

  • Controversy over oligomeric state, mass spectrometry suggests dimers
  • Simulations to model interactions with cell wall

Key Findings

  • Monomeric OMPhE: Cell wall distortion
  • Dimeric OMPhE: Stable cell wall, potential biological significance

Extended Model

  • Inclusion of Braun’s lipoprotein (most abundant protein in E. coli)
  • Impact of adding Braun’s lipoprotein on protein-cell wall interactions
  • Role of Tolar protein in binding cell wall
  • Constructing a complete virtual cell envelope: outer and inner membranes, periplasm, and associated proteins

Future Work and Unpublished Data

  • Crowding effects in the periplasm with multiple proteins and small molecules
  • Interaction of polymixin B1 antibiotic with periplasmic proteins

New Hypotheses

  • Braun’s lipoprotein’s role in protein-cell wall facilitation
  • Polymyxin B1 hitchhiking via LolA protein

Conclusion

  • Biological complexity and crowding are crucial in simulations
  • Future goal: Atomistic and coarse grain-level models of bacterial cell envelopes

Acknowledgements

  • Collaborators, group members, funding sources, computing resources
  • Group photo

Q&A Summary

  • European-wide projects: PRACE, HPC Europa
  • Eligibility: HEC Biosim for UK universities, international options available through other programs
  • General discussion: Importance of high-performance computing resources for biomolecular simulations