Research
Sumeet Agarwal
Protein Interaction Networks
I am interested in the functional organisation of protein interaction networks, and their dynamics as regulated by gene expression levels. I am looking at the use of network analysis and community detection methods for problems like protein clustering and protein function prediction.
Communities in the protein interaction network of Baker's Yeast (Saccharomyces cerevisiae)
Anna Lewis
Protein Interaction Networks
I am currently researching community structure of protein interaction networks, looking at the relationship between topological and functional properties. I am co-supervised by Nick Jones (physics) and Mason Porter (maths).
Cellular components interact with each other and can be perceived as a collection of intertwined networks which, taken as a whole, make up living systems as we know them. Much of my research concerns a statistical assessment of how network topology (the way things are wired up) is related with biological context. Ultimately, this could lead not only to a better understanding of how the cell works but also suggest ways of modelling and comparing these networks in a biologically meaningful way.
Mireille Gomes
Protein-Protein Interaction Specificity
My research focuses on how protein structure, sequence and evolution influence protein-protein interactions (PPI). I am interested in knowing how the biochemical and evolutionary properties of a protein together determine its specific interactions, and subsequently its position within protein interaction networks.
Contact Site Prediction
Konrad Krawczyk
In Silico Antibody Affinity Maturation
Antibodies make up a class of proteins indispensable in mediating immune responses. Thanks to their binding versatility immunoglobulins can recognize virtually any antigen. In a process termed 'affinity maturation', antibody interaction interfaces undergo an accelerated mutation process which accounts for the diverse binding capacities of those molecules. It goes without saying that the ability to design high-affinity specific binders is of huge interest to the pharmaceutical industry. Currently, there are not many commercial nor academic software packages (like OptCDR; Pantazes et al. 2010) which would design immunoglobulins for a specific antigen, even though proof of concept of computational antibody design was provided by Lippow in 2007. Main focus of my research is the study of the antibody affinity maturation process with the ultimate aim to produce tools which would streamline the current industrial antibody design process.
My focus is to apply computational techniques to solve real world problems. My primary area of research lies on the interface between biology, chemistry and computer science. I am interested in the holistic computational drug discovery process; especially structure based and ligand based virtual screening (VS). Together with our partners from industry we are developing methods to increase VS performance. We are currently reviewing conformer generation algorithms (image). From an applications perspective we are running a computational search for novel malaria inhibitors. Our results are chemically synthesized by our collaborators at the Latvian Institute of Organic Synthesis and biologically tested on the Plasmodium Falciparum pathogen at the Medical Research Council, London.
James Dunbar
High Resolution Modelling of Antibody Structures
My research focuses on studying and predicting the structure of the framework regions of antibody variable domains (VH and VL). The specificity of an antibody for a particular antigen is largely determined by hyper-variable loops (CDRs). However the structure of the framework which they are mounted upon is also thought to be important in determining antibody-antigen affinity. I aim to produce high resolution models of antibody molecules and study how the relative orientation of the variable domains affects the antigen binding site.
Sebastian Kelm
Structural Modelling of Transmembrane Domains
My ultimate aim is to predict the structure of membrane proteins better than any existing method. Current methods are designed for soluble proteins, which exist in a very different chemical environment. This results in low accuracy structural predictions of membrane proteins. Nevertheless, there are now sufficient amounts of membrane proteins with known structure to create an appropriate, specialised method.
Membrane insertion of the protein 1YEW (particulate methane monooxygenase of Methylococcus capsulatus).
Red: inner membrane layer;
yellow: outer membrane layer;
blue: outside the membrane
Jamie Hill
Membrane Protein Alignment / Evolution of Protein Folds
Although membrane proteins constitute up to 1/2 of all future drug targets, we have very little structural data about them. The first step in creating good (template-based) structural models is sequence-to-structure alignment. I aim to improve alignment through the use of membrane protein-specific substitution tables.
I am also interested in what the distribution of protein folds can reveal about the forces driving fold evolution. Do all extant proteins represent the narrow neck of a broadening funnel of structural possibilities, or does convergent evolution dominate with the same fold arising independently in multiple species?
I study cell-penetrating peptides (CPP) with the aim to understand what differentiates those which are cytotoxic from those which aren't. The ability of CPP to translocate cell membranes makes them particularly interesting for therapeutic applications as they could help to improve delivery and allow new classes of molecules to be considered as therapeutic agents. For this reason CPP have been extensively studied since their discovery in the early 1990s but cytotoxicity is still poorly understood and remains a major bottleneck to overcome for clinical applications. My research combines a chemometrics approach, with the aim to discriminate between membrane toxic and non-toxic CPP, and molecular dynamics (MD) simulations, to see if such discrimination can be reproduced by simulating CPP interactions with a model membrane. MD will be the primary tool to investigate CPP behavior with parallel coarse-grain simulations allowing the investigation of several peptides before using atomistic simulations for in-depth analysis. Ultimately, I'm interested in finding out whether a CPP-membrane interaction mechanism can be suggested to explain the origin of cytotoxicity. Roche USA is sponsoring the project through the Systems Approaches to Biological Science Industrial Doctoral Centre and we plan to test and refine hypotheses derived from in-silico work by using experimental cytotoxicity assays.
Henry Wilman
Membrane Protein Structure
Membrane proteins make up a significant proportion of drug targets, yet we have few experimental structures, and structure prediction is currently limited.
Currently, I am interested in distortions in transmembrane helices - what causes them, and how they might be predicted. Kinks to alpha-helices are both important to structure and function, and I hope to be able to predict the position and flexibility of these. My knowledge comes from the structures available in the PDB.
Rebecca Hamer
Bacterial Chemotaxis
I am researching into chemosensory pathways of bacteria using bioinformatics methods, with the aim of identifying the constituents of different pathways and how they interact to alter swimming direction in motile bacteria. The chemosensory pathway of E. coli has been studied extensively and is well understood. However, other bacteria have much more complicated systems with multiple pathways involving different homologues of each Che protein. Starting with the pathways in the bacterium Rhodobacter sphaeroides we plan to work out what determines which proteins interact with each other and use this information to create a model which can be used to predict chemotaxis pathways in other organisms.
Schematic diagram of the chemosensory system of E. coli.
George Wadhams and Judith Armitage,
Nature Reviews Molecular Cell Biology, Vol 5, pp1024-1037, Dec 2004
I am interested in the evolution of protein folds. Current protein structures that we have seen only occupy a small proportion of the possible configuration space. If we cluster protein structures into non-redundant folds there are many orders of magnitude fewer unique folds than there are unique sequences. What can we tell about the way evolution affects protein structure by looking at properties of these folds?
In particular, if we trace folds' occurrences across genomes in the tree of life we can establish an estimate for the relative age of each structural fold. Are there any domain properties that correlate with age and how can we use them to explore protein evolution?
Examples of common structural motifs within fold space
WR Taylor
Nature 2002 Apr 11; 416(6881): 657-60
Leila Alexander
Dynamic Properties of Protein Kinases
Protein kinases control and modulate a wide range of cellular processes. Because deregulation of protein kinases is linked to many diseases including cancer, diabetes and inflammation, they are popular therapeutic targets. In my project I aim to understand what residues determine dynamic properties of kinases using bioinformatics techniques (OPIG) and experimental methods (SGC). I hope my results would provide valuable cues to faster and more efficient drug discovery.
Structure of a typical protein kinase
Markus Gerstel
Radiation Damage in Protein Crystallography: Susceptibility Study
My project aims to improve understanding of radiation damage toproteins. The main technique of gathering detailed information aboutthe three-dimensional structure of proteins involves exposing acrystal of the protein in question to an intense X-ray beam. Duringthis experiment the sample inevitably gets damaged, which limits theresolution of the structural information that can be obtained. Thecomputational part of this project will entail statistical analysis ofdata from the RCSB Protein Data Bank and will result in hypothesesrelating specific radiation damage to local physico-chemicalparameters. In the experimental part these hypotheses will be testedagainst a family of proteins with high sequence identity and distinctmutations.
Faisal Khan
MAP Interactome Network
I am interested in looking at the process of Cell Division from a network biology perspective. My current work focuses on using an integrated protein interactions network of Microtubule-associated Proteins (MAPs) to look at the process and study the properties and functional relevance of uncharacterised proteins (putative new MAPs) present in the network. As a member of an experimental group, I am also interested to validate the findings of the MAP interactome using Cell and Molecular Biology techniques.
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