The University of Southampton
Skylaris Research Group

Vacancies

The following Ph.D. projects are available in the group. Postdoctoral positions are also occasionally available.  Interested applicants should contact Dr Chris-Kriton Skylaris (c.skylaris@soton.ac.uk)

 

 

 

NGCM-0112: New approaches for simulations of reactions in high energy materials based on large-scale first principles quantum mechanics

Project Description

High energy materials find use in many important technological applications ranging from batteries, to new fuels, to explosives. Due to their nature, these materials tend to have a high tendency to decompose and thus their long term storage and preservation poses significant challenges.

The goal of this project is to use and further develop atomistic simulation methods to understand at the atomic level the mechanisms that lead to decomposition of such materials and how these vary under different external conditions and chemical additives. For example, nitrocellulose (NC) is a high energy polymeric material which degrades by a number of different chemical processes over time. The rates of these processes depend upon the material’s particular environmental conditions. At temperatures between 100 °C and 200 °C it undergoes thermolysis at the nitrate ester groups releasing NO2. At lower temperatures, and in the presence of water, it undergoes hydrolysis to again yield NO2. The NO2 released then reacts within the binder materials generating reduced products such as NO and N2O which have been observed experimentally. However, the precise reactions which take place, how these might depend upon local conditions (such as the presence of water), and their rates (allowing for an estimation of the amount of product generated in a given time), are currently not well understood. Such problems are inherently multiscale and a hierarchy of methods need to be used to tackle the different length-scales and time-scales involved. For example, dynamics simulations with classical force fields will be used to explore the conformational space that the polymer chains can reach. At the same time, to simulate chemical reactions we will need to use methods such as first principles quantum mechanical calculations that explicitly describe the electronic rearrangements in molecules.

Conventional quantum approaches are typically limited to simulations with no more than a few tens of atoms, as the computational effort scales with the third power in the number of atoms in the simulation. However, the modelling of complex polymeric materials will require simulations with up to several thousand atoms. To achieve this we propose to use the linear-scaling DFT program ONETEP which we develop in our group and is able to perform quantum calculations with thousands of atoms. Particular challenges in this project will be the identification of possible reactions and the development of approaches to follow particular reaction paths.

The project will be supervised by Professor Chris-Kriton Skylaris at the University of Southampton and by industrial collaborators.

This project is open only to applicants who are UK nationals.


If you wish to discuss any details of the project informally, please contact Professor Chris-Kriton Skylaris, Email: c.skylaris@soton.ac.uk, Tel: +44 (0) 2380 59 9381.

This project is run through participation in the EPSRC Centre for Doctoral Training in Next Generation Computational Modelling (http://ngcm.soton.ac.uk). For details of our 4 Year PhD programme, please see http://www.findaphd.com/search/PhDDetails.aspx?CAID=331&LID=2652

For a details of available projects click here http://www.ngcm.soton.ac.uk/projects/index.html

 

 

New methods for drug design based on large-scale first principles quantum mechanics

Project Description

TMCS is an EPSRC Centre for Doctoral Training operated by the Universities of Oxford, Bristol and Southampton.
In year one you will be based in Oxford with a cohort of around 12–15 other TMCS students, and will receive in-depth training in fundamental theory, software development, and chemical applications, delivered by academics from all three Universities. Successful completion of the year-one program leads to the award of an Oxford MSc, and progression to the 3-year PhD project detailed below.

Computational simulation plays an important role in the early stages of the development of new drugs by identifying molecules (potential drugs) which can bind to biomolecular targets (e.g. sites in a protein) with high affinity and selectivity. This process involves several stages. Crude but computationally inexpensive methods (e.g. docking) are initially used to scan huge libraries of molecules and reduce the number of candidates. Eventually a small number of the “best” leads can be refined with computationally more demanding but also more accurate approaches based on classical and statistical mechanics in order to compute relative free energies of binding. This is a particularly challenging area as these methods require generating and sampling a large number of biomolecular configurations, in order to capture the entropic contribution to the binding of the drug to the target. For each of these configurations we need to have a very accurate evaluation of its energy. However, commonly used approaches depend on the use of empirical classical mechanics force fields for the generation of configurations and their energies. These have limited accuracy, as they cannot capture explicitly important energy contributions such as the electronic polarisation and charge transfer that occur in a biomolecular association event. The limitations of force fields are more severe when the molecules considered are different from the parameterisation of the force field, which is often the case when searching for new drugs.

The goal of this project is to overcome the force field limitations in biomolecular free energy calculations by employing large-scale first principles quantum chemistry calculations. To achieve this goal we will develop hybrid free energy methods which start with force fields to compute free energies of different ligands but then correct errors by computing the free energy of mutation from the classical to the quantum description. This work will build on our previous experience in this area [1,2] and will use the ONETEP linear-scaling DFT program [3], which we develop in our group with which we can do DFT calculations on entire proteins. Particular challenges in this project will be the development of free energy methods that have high configurational overlap between the classical and the quantum description and produce correct ensembles of structures. Energy Decomposition Analysis (EDA) [4] will be used on the DFT calculations to dissect the protein-drug interaction energy into chemically relevant components (such as electrostatic, exchange, polarisation, charge transfer). New EDA methods will be developed to allow the energy to be decomposed also over particular chemical functional groups, providing information for subsequent chemical modifications to improve the activity.

The new methods will be validated in actual protein-ligand targets of relevance to the pharmaceutical industry.

 

If you wish to discuss any details of the project informally, please contact Professor Chris-Kriton Skylaris, Email: c.skylaris@soton.ac.uk, Tel: +44 (0) 2380 59 9381.

 

Funding notes

Funding will be subject to normal EPSRC rules. UK and EU students will be eligible for full-fee studentships. In addition, UK students will be eligible for an annual stipend at or above £14,296 each year.

Applicants would typically be expected to have a first class degree (or overseas equivalent) in chemistry or a closely related discipline. TMCS is committed to promoting equal opportunities in science, and we particularly welcome applications from women. Applications should be made as soon as possible, but will be considered throughout the year until the programme is full. Deadlines for upcoming recruitment rounds and further information on the application process can be found at our website: View Website

Please ensure that you specify clearly that you are making a project-specific application and give the name of the project in your application.

 

References

[1] S. J. Fox, J. Dziedzic, T. Fox, C. S. Tautermann, and C.-K. Skylaris, Proteins 82 (2014) 3335.
[2] C. Sampson, T. Fox, C. S. Tautermann, C. J. Woods, and C.-K. Skylaris, J. Phys. Chem. B 119 (2015) 7030-7040.
[3] C.-K. Skylaris, P. D. Haynes, A. A. Mostofi and M. C. Payne, J. Chem. Phys. 122 (2005) 084119.
[4] M. J. S. Phipps, T. Fox, C. S. Tautermann and C.-K. Skylaris, Chem. Soc. Rev. 44(2015) 3177; M.J.S. Phipps, T. Fox, C.S. Tautermann and C.-K. Skylaris. J. Chem. Theory Comput. 13 (2017) 1837.

ONETEP

A linear-scaling code for quantum-mechanical calculations based on density-functional theory.

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NGCM PhD Programme

An EPSRC-funded doctoral training programme

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TMCS PhD Programme

An EPSRC-funded doctoral training programme

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