Biomolecular simulations

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Projects

Antimicrobial Peptide and E. coli Membrane Interactions

Syma Khalid (Investigator), Thomas Piggot, Nils Berglund

Antimicrobial peptides (AMPs) are known to disrupt the membranes of bacterial cells such as E. coli. I work on investigating the nature of these interactions using molecular dynamics (MD) simulations.

Cellular Automata Modelling of Membrane Formation and Protocell Evolution

Seth Bullock (Investigator), Stuart Bartlett

We simulate the meso-level behaviour of lipid-like particles in a range of chemical and physical environments. Self-organised protocellular structures can be shown to emerge spontaneously in systems with random, homogeneous initial conditions. We aim to take the current model further and explore more complex chemical scenarios in which a broad range of evolutionary behaviours will be exhibited.

Development of wide-ranging functionality in ONETEP

Chris-Kriton Skylaris (Investigator), Jacek Dziedzic

ONETEP is at the cutting edge of developments in first principles calculations. However, while the fundamental difficulties of performing accurate first-principles calculations with linear-scaling cost have been solved, only a small core of functionality is currently available in ONETEP which prevents its wide application. In this collaborative project between three Universities, the original developers of ONETEP will lead an ambitious workplan whereby the functionality of the code will be rapidly and significantly enriched.

Electrostatic embedded energy calculations of proteins, using the ONETEP DFT code

Chris-Kriton Skylaris (Investigator), Stephen Fox, Chris Pittock

Calculating the energy of a biomolecule in solvent, using quantum mechanics (QM) is possible, but extremely challenging, even with linear-scaling QM methods like ONETEP. Using electrostatic embedding, a novel twist on the existing QM/MM method is used to calculate the binding energy of a small ligand to a solvated protein, increasing the accuracy and realism of our general project work.

How far can we stretch the MARTINI?

Syma Khalid (Investigator), Ric Gillams

To date, coarse-grained lipid models have generally been parameterised to ensure the correct prediction of structural properties of membranes, such as the area per lipid and the bilayer thickness. The work described here explores the extent to which coarse-grained models are able to predict correctly bulk properties of lipids (phase behaviour) as well as the mechanical properties, such as lateral pressure profiles and stored elastic stress in bilayers. Such an evaluation is crucial for understanding the predictive capabilities of coarse-grained models.

Hybrid quantum and classical free energy methods in computational drug optimisation

Jonathan Essex, Chris-Kriton Skylaris (Investigators), Christopher Cave-Ayland

This work is based around the application of thermodynamics and quantum mechanics to the field of computational drug design and optimisation. Through the application of these theories the calculation of the physical properties of drug-like molecules is possible and hence some predictive power for their pharmaceutical activity in vivo can be obtained.

Immunotherapy Research: Modelling MHC Class I Complex Assembly

Timothy Elliott, Jorn Werner (Investigators), Alistair Bailey

This project uses mathematical modelling and simulation to investigate mechanisms by which our cells process and present biological information that is used by our immune system to distinguish between healthy and diseased cells.

Measuring biomolecules - improvements to the spectroscopic ruler

Pavlos Lagoudakis, Tom Brown (Investigators), Jan Junis Rindermann, James Richardson

The spectroscopic ruler is a technique to measure the geometry of biomolecules on the nm scale by labeling them with pairs of fluorescent markers and measuring distance dependent non-radiative energy transfer between them. The remaining uncertainty in the application of the technique originates from the unknown orientation between the optical dipole moments of the fluorescent markers, especially when the molecule undergoes thermal fluctuations in physiological conditions. Recently we introduced a simulation based method for the interpretation of the fluorescence decay dynamics of the markers that allows us to retrieve both the average orientation and the extent of directional fluctuations of the involved dipole moments.

Molecular Fragments in Inhibitor Design

Jonathan Essex (Investigator), Michael Bodnarchuk

Fragment-Based Drug Discovery (FBDD) has emerged as an important tool in the drug discovery process. Instead of screening entire drug molecules, FBDD screens molecular fragments; constituents which make up drug molecules. A computational approach to identifying fragment binding is currently being sought which also yield binding free energy estimation.

Multi-scale simulations of bacterial outer-membrane proteins

Syma Khalid (Investigator), Jamie Parkin

Using Iridis to run multiple simulations, I aim to simulate the outer membrane proteins of Pseudomonas aeruginosa, using X-ray crystal structures of proteins only recently resolved by Bert van den Berg, University of Massachusetts. By modelling the proteins in a realistic P. aeruginosa outer membrane, I am to gain insight into the binding of these proteins to specific substrates and their function.

Probing the oligomeric state and interaction surface of Fukutin Transmembrane Domain in lipid bilayer via Molecular Dynamics simulations

Nils Berglund

Fukutin Transmembrane Domain (FK1TMD) is localised to the endoplasmic reticulum or Golgi Apparatus within the cell where it is believed to function as a glycosyltransferase. Its localisation within the cell is thought to be mediated by the interaction of its N-terminal transmembrane domain with the lipid bilayers surrounding these compartments, each of which possess a distinctive lipid composition. Studies have revealed that the N-terminal transmembrane domain of FK1TMD exists as dimer within dilauroylphosphatidylcholine bilayers and this interaction is driven by interactions between a characteristic TXXSS motif. Furthermore residues close to the N-terminus that have previously been shown to play a key role in the clustering of lipids are shown to play a key role in anchoring the protein in the membrane.

Sustainable domain-specific software generation tools for extremely parallel particle-based simulations

Chris-Kriton Skylaris (Investigator)

A range of particle based methods (PBM) are currently used to simulate materials in chemistry, engineering, physics and biophysics. The 4 types of PBM considered directly in the proposed are molecular dynamics (MD), the ONETEP quantum mechanics-based program, discrete element modelling (DEM), and smoothed particle hydrodynamics (SPH).
The overall research objective is to develop a sustainable tool that will deliver, in the future, cutting edge research applicable to applications ranging from dam engineering to atomistic drug design.

Water Molecules in Protein Binding Sites

Jonathan Essex (Investigator), Michael Bodnarchuk

Water molecules are commonplace in protein binding sites, although the true location of them can often be hard to predict from crystallographic methods. We are developing tools which enable the location and affinity of water molecules to be found.