List of Project Titles for PPS '17-'18
Note: Make sure you read the paragraph describing each project carefully before making your choice. You are encouraged to describe and discuss
the principles of their selected topic in detail, rather than to provide an exhaustive list of examples. Students who produce their own clear, relevant
diagrams using appropriate software will be marked significantly higher than those who copy equally relevant diagrams from elsewhere. The sources of any
copied diagrams MUST be clearly acknowledged.
1. Protein motif and domain databases
There are now many databases that hold information about protein motifs and domains with known function, including sequence alignments. Evaluate and
compare the holdings of the protein motif/domain database Prosite and the domain databases Pfam, ProDom and SMART in terms of their coverage, ease of use,
depth of coverage of each protein family, and the accuracy of the information provided. Explain how the information in each is derived. How much does the
entry for a typical family in each database tell the user about these proteins' structures?
2. Recent structures of haemoglobin
Haemoglobin was one of the first two protein structures to be solved by X-ray crystallography, and this technique is still revealing more information
about the structure and mechanism of this protein. Survey the structures of proteins in the haemoglobin family still available in the PDB, concentrating on
recent high-resolution ones. How have these recent structures contributed to our understanding of the evolution and mechanism of action of these proteins, and
of diseases such as sickle cell anaemia and the thalassemias? How has the increase in resolution of these structures over the decades affected the
quality and value of the information derived from them?
3. The exosome complex
The exosome complex is a macromolecular complex that is involved in the degradation of RNA. Describe the mechanism and the biological role of this
complex and relate this to the structural details of the macromolecular cage utilized in the controlled degradation of RNA. Compare and contrast this
structure with that of the proteasome, which plays a similar role in the degradation of proteins.
4. Protein sequence alignment
Describe and explain the algorithms used both in pairwise and in multiple alignments of protein sequences. How can the precision, accuracy and utility
of such an alignment be evaluated? Describe a range of bioinformatics programs and techniques that rely on multiple alignments, focusing on the importance
of the quality of that alignment for the validity of the results. Decsribe how multiple alignments are used in other bioinformatics applications,
particularly those for predicting the structures of proteins.
Oxytocin is a mammalian peptide hormone that has been associated with the neurobiology of pair-bonding and sexual reproduction; it is sometimes referred
to as a "bonding hormone". Describe in detail the production of this hormone from gene to active molecule. Include discussions of the structural
features of the isolated hormone, the carrier protein neurophysin and bound complexes of the two as the gene product is processed biologically.
6. Insulin and insulin-like growth factors
The small hormone insulin was one of the first proteins to have its structure determined. Describe what we have learned about its structure and mechanism
of action in the decades since it was first determined. Compare and contrast its structure and function with that of the the insulin-like growth factors
[IGFs]. Explain how these polypeptides feature in human diseases. How has our knowledge of their structure contributed to the development of therapies
for these diseases?
7. Gene duplication
Gene duplication is an important evolutionary mechanism for generating gene and protein diversity. Using human genes and proteins as examples,
describe in detail the role of this process in the evolution of protein structure and function. Your dissertation should include examples taken from single
domain and multi-domain protein chains, protein monomers and oligomers and protein families.
8. Ion channels
Many different families of proteins have evolved to allow both positively and negatively charged ions to flow passively across cell and organelle
membranes. Describe the structure, function and mechanism of each of the ion channel families of known structure that have at least one representative in
the human proteome, and describe how mutations in some of these proteins give rise to disease.
9. Human serum albumin
Human serum albumin [HSA] is the most abundant protein in blood plasma. It acts as a key transporter for small molecules in the bloodstream including
fatty acids and drugs and contains a number of bound metals. Survey the full range of protein structures of HSA that are available in the PDB and relate
these to the known biological functions of the binding sites on the HSA protein structure. What post-translational modifications to HSA have been observed,
and what effect do they have on the protein's structure and function? Explain the role that some of these play in human disease.
10. Cryoprotectant proteins
Cryoprotectants allow organisms to resist freezing and the formation of ice crystals if the temperature moves to below freezing. Survey the
cryoprotectant proteins that fish and insects use to prevent damage due to extreme cooling; describe their structures where this is possible and explain
how the structures determine these proteins' unusual function.
11. Symmetry in protein crystal structures
The PDBe contains a database of the symmetry of all deposited crystal structures which can be found from http://www.ebi.ac.uk/msd-srv/prot_int/pistart.html. Take as examples some of the oligomeric states with unusual symmetries (less than 100 representatives in this database) and describe the symmetries
that arise. For each case, discuss whether and how the unusual oligomeric state contributes to the function of the protein concerned.
12. Drug targets for malaria
Malaria still causes over half a million deaths each year, despite the widespread availability of drugs. Describe the structures of proteins from the
malaria parasite, Plasmodium falciparum in the PDB. Which of these have been used as targets for anti-malarial drugs? Describe the structures and
mechanisms of a number of anti-malarial drugs with targets with known structure, including, if possible, drugs in development. Describe and explain using
examples the properties that you would expect an ideal anti-malarial drug target to have.
13. ApoE mutations
Describe the structure and the diverse functions of the human protein apoliprotein E (ApoE). Describe the range of diseases that are caused
by mutations in the gene encoding this protein and discuss the likely impact of the mutations on the encoded protein using examples. Discuss the association
of ApoE genotypes with risk for coronary heart disease. You may find it useful to register with The Human Gene Mutation Database
14. Recognition of peptidoglycan fragments for signalling
Peptidoglycan forms a major part of the bacterial cell well. Fragments released from the membrane by enzymes are used by bacteria for their own
signalling and by insects and mammals for their immune responses. Review the literature on the structures and, as far as is known, the mechanisms of modules
that recognise peptidoglycan subjects for signalling.
15. Nobel Prizes for structural biology
http://proteopedia.org/wiki/index.php/Nobel_Prizes_for_3D_Molecular_Structure five or six cases where the Nobel Prize was given for the elucidation of
a structure and consequent explanation of the function of one protein or protein family. Describe the structure and function of your chosen proteins and
explain the contribution that its discovery has made to drug development and/or to structural biology more generally.
16. Kinase inhibitors
Inhibitors of the kinase enzymes that add phosphate groups to proteins are now some of the most important and widely used anti-cancer drugs, but their
utility is often compromised by mutation in the kinase targets. Describe the structure and function of the protein kinases and the mechanism of action of
their inhibitors. Explain the molecular mechanisms for the development of resistance in detail with reference to a range of structures of wild type and
mutated kinases bound to small molecules.
17. The hydrophobic effect
The hydrophobic effect is thought to be the most important non-covalent interaction that determines protein folding. Explain in detail how this theory
has developed throughout the twentieth century and explain its importance in protein folding. How have structural studies of the network of water molecules
close to protein crystal structures contributed to this? Refer to some examples of recent high resolution structures in your explanation.
18. Ebola and Zika virus structures
Describe what we have learned about the structure of the proteins that make up the Ebola and Zika viruses, including the symmetry of the viral coats,
and explain how these structures were determined. Describe the similarities and differences between these viruses and closely related ones of known structure.
Explain how our knowledge of these structures can help in the development of drugs and vaccines for these devastating emerging diseases.
Some RNA molecules can act as catalysts, and these 'RNA enzymes' are termed ribozymes. Structures have been determined for a number of ribozymes,
including RNA components of the ribosome and spliceosome as well as small, isolated RNA molecules. Catalogue the structures and functions of the ribozymes
of known structure, describing their mechanisms where this is known and explaining their biological roles.
20. Tissue transglutaminases and protein cross-linking
Tissue transglutaminases have an important role in cross-linking proteins, but this cross-linking can lead to problems like the development of celiac
disease. What is our current understanding of the wide range of roles that the transglutaminases hold? Compare and contrast this system with other types of
crosslinks used to strengthen protein complexes, e.g. Cys-Cys bonds in antibodies and the enzymes that build peptide networks that protect bacteria.
21. Lead-protein binding
Lead ions act as poisons by blocking the normal function of a number of different proteins in the body. This can be particularly serious in young children
causing neurological damage. Anaemia is also seen as a result of lead poisoning by blocking the production of heme required for normal red cell production.
Displacement of Ca and Zn ions by Pb can be detrimental in some systems, e.g. calmodulin and signalling. Survey the mechanism and chemistry of
lead-protein binding and describe the structures and functions of metalloproteins that can be damaged in this way.
22. Molecular Machines
Explain what is meant by the term 'molecular machine'. Describe in detail the structures, functions and mechanisms of a number of molecular machines
with known 3D structures that are involved in different physiological functions. Explain how a knowledge of the atomic structures of these machines have
helped us understand their role in biology and, where applicable, how their function can be affected by drugs.
23. Cystic Fibrosis
Cystic fibrosis is one of the most common serious diseases that exhibits classical Mendelian inheritance; that is, it results from mutations in a
single protein. That protein is the cystic fibrosis conductance regulator (CFTR). Describe the domain and 3D structures of this protein in detail and
explain how our growing knowledge of this has contributed to our understanding of the disease. Explain how strategies for combating different forms of
the disease are emerging from this structural information.
24. Secondary Structure Prediction
Programs to predict the secondary structures of proteins were some of the first bioinformatics tools to be developed. Survey the development of these
programs from the beginnings of structural bioinformatics to the present day. Explain how each program or type of program works and present a detailed
comparison of the precision and accuracy of the results obtained by each. How are secondary structure predictions currently used and what extra value can
the technique add now over 100,000 experimentally-determined structures are available?
Please refer to the project guidelines before choosing your project.
Clare Sansom & Jim Pitts, June 2017