This broad programme of research is carried out by applying computational and mathematical technology for both the development and application of algorithms and analysis of molecular biology data. Often this data is large-scale, for example including the genome sequences of thousands of people or thousands of different organisms. Other examples of data types include the 3D structure of proteins, networks of interactions between proteins, gene expression, etc. By taking datasets produced by many experiments, using computers we are able to: answer fundamental questions such as how evolution takes place at the molecular level, and what are the genetic determinants of human phenotypes; answer questions of practical importance such as how to reprogram one human cell type into another for regenerative medicine; and to invent computational tools and techniques that enable others to answer questions of fundamental and practical importance in biology.

Natural infection with many viruses results in the production of antibodies which help clear the virus and protect us from subsequent reinfection. Eliciting such a response is the basis of many effective vaccines, but unfortunately little is understood about protective antibody responses in HIV, which has hindered HIV vaccine design. Despite sharing many similarities with HIV-1, most patients with HIV-2 do not develop AIDS (although a minority do) and the reasons for this are not entirely clear. This project proposes to compare neutralizing antibody responses in HIV-1 and HIV-2 infection and explore whether stronger responses are found in HIV-2 infected patients who do not progress to AIDS, when compared to HIV-2 progressors and HIV-1 patients.||Early studies also suggested that HIV-2 antibodies could render HIV-1 non-functional and although some previous studies claimed HIV-2 infected individuals may be protected against subsequent HIV-1 infection, the majority suggest no protection or even an increased risk of acquiring HIV-1 superinfection. We therefore propose to compare HIV-1 cross-neutralizing antibody responses and enhancing antibody responses in HIV-2 patients who go on to acquire HIV-1 superinfection, with those who have remained HIV-2 mono-infected despite possible exposure to HIV-1.||Such information could provide vital clues to how the HIV surface interacts with antibodies and the importance of eliciting an antibody response in future HIV vaccines.

Nerve cells (neurons) communicate (via neurotransmitters) at specialized cell junctions called synapses. During synaptic transmission, neurotransmitter released from the presynaptic neuron activates receptors at the postsynaptic neuron, thereby converting a chemical signal (neurotransmitter) into a rapid electrical response. The major transmitter in the mammalian brain is glutamate, which acts on various types of receptors. AMPA-type glutamate receptors (AMPARs) are the fastest transmitter-gated receptors in the brain, permitting precise information transfer. AMPARs are also essential for the expression of synaptic plasticity, a process underlying learning and information storage in the brain. Malfunction of these receptors underlies various neurological disorders. AMPAR signalling is diverse which is largely due to the existence of different AMPAR complexes, which assemble in various combinations, in a poorly understood process. This early event in receptor ontogeny is central as it ultimately determines the efficacy and plasticity of glutamatergic signal transmission. AMPAR action occurs on the millisecond time scale, and accurate signalling requires the receptor to be located precisely opposite presynaptic transmitter release sites. Our work showed that an extracellular AMPAR segment, the N-terminal domain, is essential for receptor positioning most likely by interacting with to-be-identified synaptic cleft proteins. Since the NTD is highly sequence-diverse between AMPAR subunits it will mediate subtype-selective ‘synaptic anchorage’ which provides a mechanism to fine-tune signal transmission. The aim of our research is to shed light on the assembly mechanism, to characterise functionally diverse AMPAR complexes structurally allowing precise intervention, and to follow their fate during synaptic potentiation using electrophysiology and imaging approaches. We anticipate that this combined approach will permit unprecedented insight into the process of information storage at synapses in the brain.