Application deadline: 3rd March
Interviews to be held: 31 March 2021
One of the key engineering challenges in the life-science and biomedical sectors is the design and manufacturing of bespoke scaffolds for 3D cell culture, tissue engineering and cell/drug delivery, i.e. cell niches. These cell niches underpin a large and growing sector of biotech and biomed industries whether they are used (i) in-vitro for the study of cell behaviour, toxicity testing or tissue engineering, or (ii) in-vivo for the delivery of cells and/or drugs or to promote regeneration of damaged tissues. In the past two decades significant efforts have been made to develop novel biomaterials to build such scaffolds. One such class of material, which has attracted significant interest, is hydrogels as these soft, highly hydrated materials can be engineered to mimic the cell niche. A variety of approaches can be used to design hydrogels, including the self-assembly of short de-novo designed synthetic self-assembling peptides.
Peptides offer a number of advantages:
(i) peptide synthesis has become a routine procedure making them easily accessible.
(ii) the library of 20 natural amino acids offers the ability to modulate the intrinsic properties of the peptide such as structure, hydrophobicity, charge and functionality, allowing the design of materials with a wide range of properties.
(iii) synthetic peptides are chemically fully defined and easy to purify through standard processes, which is not always the case for natural polymers such as proteins.
(iv) being built from natural amino acids they usually result in low toxicity and low immune response when used in-vivo, and can be degraded and metabolised by the body, which is not always the case for synthetic polymers.
One of the most popular and successful design, as far as hydrogel formation is concerned, was devised by Zhang’s group and is based on short peptides (4 to 20 amino acids long) with alternating hydrophilic and hydrophobic residues.
Main question to be answered
The gelation of a short peptide is a two-stage process. First, the peptide needs to be able to self-assemble into fibrillar structures, which in a second step need to entangle and/or associate to form 3D percolated networks that retain water. The early-stage conformational pathway dictates the nature and morphology of the fibrillar structure formed ultimately defining the final properties of the materials.
In this project we computationally investigate, starting from basic principles and using the state-of-the-art approach Quantum Chemical Topology (QCT), the chemical peptide design space (in terms of peptide sequence, property of individual amino acid and conformation space) in the context of b-sheet fibrillation prediction.
The figure shows the so-called topological atoms appearing in two anti-parallel β strands, engaging in hydrogen bonding. The atoms are space-filling (finite volumes) and their specific properties (charge, energy, dipole moment), can be calculated for any configuration. This modern view of atomistic reality offers two activities: interpretation and prediction of structure and dynamics. The former involves: (i) quantification of the local strength of hydrogen bond interaction by quantum topological measures, (ii) Relative Energy Gradient (REG) analysis of rotational energy barriers in the peptide backbone, (iii) electrostatic field analysis of fibril surfaces, and (iv) characterisation of edge effects (“sticky junction”) in terms of electron correlation/dispersive effects in pi-pi stacking.
The latter activity (prediction) plucks the first fruit of a completely new force field called FFLUX, which has been designed from scratch over the last decade in order to make a step change in accuracy. It’s more reliable architecture, and involvement of machine learning, guarantees long term success in understanding fibril formation, and thus serves as a rational guide to future peptide design
EPSRC Centre for Doctoral Training in Advanced Biomedical Materials
This project is part of the EPSRC Centre for Doctoral Training in Advanced Biomedical Materials. All available projects are listed here.
Find out how to apply, with full details on eligibility and funding here.
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