Design of Multifunctional Nanoparticles
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
This project will involve theory and simulation to discover necessary and sufficient conditions for design of multifunctional nanoparticles using a coarse-grained approach. The conceptual and computational tools of energy landscape theory will be employed to characterise systems with competing funnels corresponding to locally stable morphologies. The competing structures will be designed so that external effects such as electric and magnetic fields or temperature and pressure can be applied to switch between them. The local rigid body framework will be exploited within the GMIN, OPTIM and PATHSAMPLE programs, along with flexible interparticle potentials, such as the PY model, which has previously been shown to support structures that range from shells to tubes. This framework will be extended to admit sites that can move within the underlying framework, providing a model of patchy particles where the patches can move over a well-defined surface.
To optimise the functionality we will employ an extended Hamiltonian approach, where the additional degrees of freedom, corresponding to internal rearrangements of the building blocks, are treated on the same footing as the rigid body coordinates. This will involve both new theory and programming for the internal degrees of freedom.
To optimise the functionality we will employ an extended Hamiltonian approach, where the additional degrees of freedom, corresponding to internal rearrangements of the building blocks, are treated on the same footing as the rigid body coordinates. This will involve both new theory and programming for the internal degrees of freedom.
People |
ORCID iD |
| David John Wales (Primary Supervisor) | |
| Alasdair Keith (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509620/1 | 01/10/2016 | 30/09/2022 | |||
| 1944583 | Studentship | EP/N509620/1 | 01/10/2017 | 30/09/2021 | Alasdair Keith |
| Description | The research funded with this award can be split into two components. 1. This concerns the analysis of virus capsids using coarse-graining computational methods. A previously reported [doi:10.1039/b818062h] set of rigid bodies was used to investigate the maturation of a T=7 capsid, HK97. However, it soon became clear that this model (which was designed to be applicable to capsids of T=3 symmetry) was not suitable for the bigger T=7 capsids. This resulted in a preponderance of artificial minimum structures. 2. This second project bridges theoretical and experimental chemistry, and is a collaboration between the Barker and Wales groups. The Barker group had been studying the protein, HemS, where they discovered that it can break down haem in a novel oxygen-independent process using NADH. However, they could not identify key binding sites for NADH in the protein pocket with X-ray crystallography due its transient nature. Therefore, a bioinformatics package was used to identify likely binding sites. Then, using the Wales group's custom-built suite of programs, these binding sites were connected to one another using basin-hopping and discrete path sampling. This gave a multitude of pathways showing how NADH can move along the pocket to approach haem. The advantage of these techniques over standard molecular dynamics simulations is that they calculate real transition states so that a valid kinetic analysis, as well as thermodynamic analysis, can be made. The pathways calculated suggested various residues to be key to facilitating the movement of NADH along the pocket towards haem. This has informed experiment so that targeted mutations could be made to the protein, and the effects of such mutations on the ability of the protein to break down haem analysed. This work is currently ongoing. In parallel to this, a computational study is underway, whereby the stationary points in the wild type database are reoptimised with mutations in place to see how the mutations effect the overall kinetic and thermodynamic properties of the system, and in particular on the fastest pathways showing NADH approaching the haem. This work is a novel collaboration between experiment, bioinformatics and theory. Computations have suggested various mutations to make to HemS that experiment simply could not have gleaned. Should these mutations turn out to be important, this could spell a novel method to target residues for mutations aside from standard experimental techniques, such as directed evolution. Preliminary results are promising - for example, the computational methods have correctly identified the hydride which NADH transfers to the haem in the reaction's first step. Furthermore, it is believed this is the first time that the Wales group methods have been used to study the interactions between a protein and its various cofactors. 2021 Update: Mutagenesis study (experimental) is nearing completion. Data would suggest the mutations of some of these residues, as identified by computations, have interesting impacts on the rate of reaction. The scope of this project was expanded significantly by the inclusion of an analysis of relevant homologues of HemS (these being ChuS, Shus and HmuS). This involved an expansion of the computational methods used to mutate residues, to allow for many residues within the one system to be mutated in parallel. This has been done in conjunction with an experimental investigation into these homologues, giving us a better understanding of the complex roles of these haem-sequestering proteins. |
| Exploitation Route | It is envisaged that the outcomes from this funding could be taken forward in two different ways. The first would be by the biological/pharmaceutical community. Since HemS belongs to the Yersinia enterocolitica - a bacterium often found in poor water supplies in the developing world, and implicated in many adverse effects such as fever and fatal sepsis - and is thought to be one of the key proteins responsible for the above-listed adverse effects, any study into how it actually operates could prove important for those wishing to develop drugs to prevent such effects. The second potential for taking outcomes forward relates to the interplay between experimental and theoretical chemistry. This is becoming increasingly important in the field of chemistry as using computations to make predictions about chemical systems can prove both cost- and labour-efficient. Using the Wales group methods to make predictions about enzyme-cofactor interactions - until now, such methods have typically only been used for non-biological or in protein folding problems - is fairly novel but could have wide-ranging pharmaceutical implications. 2021 Update: The expansion of this project to include homologues of HemS is also important as it provides a wider context to this research. Many types of bacteria contain haem-sequestering proteins, but knowledge of their functions and wider role in the cell is often sparse. This research, once published, should go some way to bridging that gap. For example, one of the homologues being studied is ChuS, which is native to E.coli, a very important and widely-used bacterium in biochemistry. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Title | Wales Programs GMIN, OPTIM and PATHSAMPLE as applied to protein-cofactor interactions. |
| Description | The programs GMIN, OPTIM and PATHSAMPLE have been available for public use for over 20 years. They are under continuous development by the Wales group and have been used to model/solve questions involving many non-biological systems as well as protein-folding problems. They have an advantage over standard molecular dynamics in that they can calculate real transition states, thus allowing for kinetic as well as thermodynamic profiles for a system to be developed. In the research I have conducted using this grant, I have extended the use of these three programs (interfaced to AMBER) to address problems involving protein-cofactor interactions. This involves an analysis of the non-covalent interactions between the cofactor atoms and relevant residues of the protein. |
| Type Of Material | Improvements to research infrastructure |
| Provided To Others? | Yes |
| Impact | GMIN, OPTIM and PATHSAMPLE have already had a significant impact in the Energy Landscapes field. They have also proven to be capable of predicting the behaviour of certain biological system (usually, how proteins fold) thus impacting the biochemical field too. It is hoped that my work in protein-cofactor interactions will allow these programs to impact the biochemical field still further. |
| Description | Experimental HemS collaboration with Paul Barker |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | In addition to my primary supervisor, Professor David Wales, I now have a second supervisor, Dr Paul Barker. With him, I've undertaken the experimental part of my current HemS project. 2021 Update: This project has now expanded to include an investigation into various homologues and mutants of HemS. |
| Collaborator Contribution | Dr Paul Barker has expertise on the Hem system, and in particular on the HemS protein. My work is currently building on research previously undertaken by some of his former students. |
| Impact | All those involved in this collaboration work in the Department of Chemistry at the University of Cambridge. The collaboration has allowed for an analysis of the HemS protein from both an experimental and a computational perspective. Some papers should be forthcoming by the end of this calendar year. 2021 Update: There is now a bioinformatics aspect to this project, being carried out by myself and others in the Barker group. The publication of papers has been delayed but should be ready for submission by September of this year. |
| Start Year | 2018 |