The results from Giulia's biomolecular simulations explain experimental observations made by our long-standing collaborators Arnaud Javelle and Anna-Maria Marini to yield key insights into the variations of substrate specificity and the type of mechanism for transporting ammonium in Mep-Amt-Rh proteins. Importantly, only one of these, Mep2, is capable of triggering filamentation in yeast, leading to infection. The findings have been published in mBio.
Molecular Simulations of Membrane Protein Function
Biological cells enable the processes of life to occur within small, highly controlled compartments far from equilibrium. Cells are bounded by biomembranes, which are impermeable to many solutes and present a barrier to the exchange of matter and information between the outside and the inside of the cell. Since life requires a constant flux of matter and energy, specialized proteins have evolved that enable the transfer of ions, molecules, and signals between the cell and the external world. These processes are of such central importance for the life of cells that, in humans, about one-third of the genome encodes membrane proteins and almost one-half of all marketed drugs target membrane proteins.
A core interest of the group are the molecular mechanisms of membrane protein function, their interaction with drugs and substrates, and their wider environment inside lipid bilayers. Key present examples are membrane ion channels (e.g. the ion conduction efficiency and selectivity of potassium channels), pores in the outer membrane of bacteria that are found to be mutated in bacterial strains resistant to antibiotics (e.g., neisserial PorB), membrane surface receptors such as G-protein coupled receptors (e.g. muscarinic and opioid receptors), and membrane transporters such as multidrug efflux pumps or AmtB. Often, we are especially interested in the role of realistic membrane potentials in the function of these proteins.
Biomechanics of Tandem Repeat Proteins
Proteins form the machinery of biological cells. A large proportion of the proteome in higher organisms consists of solenoid repeat proteins, in which small conserved structural units stack to yield extended structures with large water-exposed surfaces. These proteins often play a role in enabling tight protein-protein binding interactions or they can serve as structural scaffolds. Depending on the fundamental repeating unit, they can be classified as HEAT, leucine-rich, tetratricopeptide, ankyrin or armadillo repeat proteins. In alpha-helical solenoid proteins, the building blocks usually consist of two to three alpha-helices. Alpha-solenoids such as HEAT repeat proteins are often exceptionally flexible and elastic, features that are key to their biological functions. In recent years, we have focused on tetratricopeptide (TPR) domains (shown here), studying their biomechanics and the role of changes in TPR dynamics in human disease.
Join the Team
Several PhD studentships in the area of computational biophysics, molecular modelling and simulations as well as chemoinformatics/machine learning
are available in the group.
The positions are fully funded through MRC, BBSRC and Wellcome Trust PhD programmes.
For more information, see Jobs and follow the link there.
We are looking for biochemists, chemists, biologists and physicists interested in working at the interface between the traditional disciplines. Contact us if you are interested in studying the mechanisms that drive biology with a view to developing drugs - and if you like computational work. For a clearer picture, read more about our past and present research and have a look at our publications.