Coordinator: A/Prof Jackie Wilce
Bioinformatics unites the major advances in biology, biochemistry and the biomedical sciences with those in computing, bioinformatics and networking. The unit covers the application of the internet to biomedical sciences; organisation and uses of scientific databases; use of computational methods in genomics and proteomics; fundamentals of molecular modelling; analysis and presentation of biomedical data; and communication of biomedical data using information technology.
BMS2062 focuses on the relationships between the structures and functions of biological macromolecules (DNA, RNA, and proteins). Building on knowledge of molecular biology (BMS1062) and protein structure (BMS1011), the lecture course will explore the many ways in which regulation of biomolecular activity is critical to biological function. A variety of situations in which failure of these mechanisms gives rise to human disease will be discussed. Modern research into biomolecular function takes advantage of rapidly growing databases of biomolecular sequences, structures, and properties. In the practical course, students will become familiar with a variety of bioinformatics tools and approaches for extracting useful functional and evolutionary information from these databases. The Disease Protein Assignment will provide an opportunity to combine the theoretical and practical aspects of the unit.
|A/Prof Jackie Wilce, Coordinator||Dr George Kotsanas||Prof Phil Bird|
|Dr Dieter Bulach||Dr Craig Morton||Assoc Prof Martin Stone|
|Assoc Prof Matthew Wilce||Dr Michelle Dunstone|
Organisation of the Unit
BMS2062 consists of 2 lectures per week, one 3 hour computer laboratory session per week.
Enrolled students can access timetables, lecture notes and supplementary material on the BMS2062 Blackboard site.
PART I. THE CENTRAL DOGMA OF MOLECULAR BIOLOGY
Review of Biopolymer Structure & Function
The central dogma of molecular biology is that DNA sequence gives rise to RNA sequence, which gives rise to proteins and hence cellular and higher order function (phenotype). We will expand on this paradigm by discussing the various ways in which DNA, RNA and proteins can be modified or controlled to regulate their functions and the importance of these regulatory mechanisms in health and disease. The Disease Protein Assignment is a major activity of this unit that draws upon these concepts.
It's Written in Your Genes: The Language of DNA
Over the last half‐century, a picture of the biological information contained in DNA has been built up, allowing bioinformaticians to rapidly scan new DNA sequences looking for patterns that reveal genes, protein binding sites, viral insertions and structural elements. In this lecture, we will review the structure, function and organization of DNA. Emphasis will be placed on sequence motifs that can be found in DNA, and how these contribute to our understanding of DNA function and information flow in the cell.
Not Just a Messenger: RNA Origami
We will review the structure and function of RNA. Information encoded in DNA flows to messenger RNA and eventually to proteins. Besides being an information carrier, RNA plays a pivotal role in the machinery replicating and regulating genes, and driving protein synthesis. The latter functions of RNA largely depend on its ability to form complex secondary structures and bind proteins, and predicting these structures de novo remains a challenge for bioinformatics.
PART II. GENES & GENOMES: SEQUENCE VARIATION AND ANALYSIS
Unlocking an Organism's Genetic Potential through Genome Sequencing
The entire genetic potential of an organism is locked within the DNA sequence of its genome. Therefore, if you can determine the genome sequence of an organism you have the basic information on how the organism functions at the molecular level. We discuss strategies for determining the sequence of bacterial genomes, including some very recently developed technologies. We also discuss basic methods for identifying the important information stored with the genome sequence including the identification of open reading frames, transcriptional regulatory elements, tRNA and rRNA genes, mobile genetic elements and repetitive DNA sequences.
Bacterial Antibiotic Resistance and Expression of Virulence Factors
The comparison of sequenced bacterial genomes can be used to identify genes involved in specific phenotypic traits of critical importance to bacterial survival. We show how genes involved in antibiotic resistance or virulence can be identified by whole genome sequencing of highly related bacterial strains. We discuss how genetic differences can be identified and how putative functions of specific genes can be inferred.
The Human Genome Project
Sequencing of the human genome has been completed. Bioinformatics has played a key part in the Human Genome Project (HGP), and will be central to exploiting the vast amount of data it has generated. Here we look at the achievements of the HGP and the implications for future biomedical research. We will consider how protein‐coding genes are identified amongst the background of non‐coding and junk DNA.strong>PART III: FROM GENOTYPE TO PHENOTYPE
Avoiding Fool's Gold. How Do We Prove that Virtual Genes Are Real?
Although the entire genetic blueprint is present in every nucleated cell, not every gene is switched on in every cell, and some genes are switched on or off according to developmental or disease state. Thus full understanding and exploitation of the human genome data requires complementary methods to determine whether newly‐identified (hypothetical) genes are real, and when and where specific genes are expressed. This is usually done by determining when and where their mRNAs are produced.
Backwards and Forwards: Strategies for Working Out What Genes Do
Many genes identified by genome sequencing projects are hypothetical, in that there is no experimental evidence to suggest that they are functional. Other genes encode products whose biological functions are unknown. We will look at key experimental approaches used to assess gene function.
What Makes an Individual? Genome Fingerprinting, Faster Sequencing & the Route towards Personalized Medicine
No two individuals have exactly the same genomic sequence, and genetic differences between individuals underpin differing susceptibility to disease, and can influence the response to treatment. Faster sequencing and array technologies now under development promise a future in which an individual's genotype can be rapidly and cheaply determined. Single nucleotide polymorphisms (SNPs) account for most of the differences between individuals, and the analysis of associations between SNP patterns and disease susceptibility illustrates how such information might be exploited to "personalize" medicine.
PART IV: PROTEIN EXPRESSION AND MODIFICATION
Translation: From mRNA to Protein
Translation, the interpretation of mRNA sequences to yield protein sequences, is carried out at the ribosome, a sophisticated molecular assembly consisting of RNA and protein components. This lecture will discuss the major components of the translation machinery and the major steps in the translation process.
Protein Families: What Can They Teach Us?
The amino acid sequences of proteins dictate their three-dimensional structures and therefore their biological functions. Therefore, amino acid residues that are important for structure and function are maintained throughout the course of evolution. By comparing their sequences, it is possible to identify proteins with similar structures and functions (i.e. protein families) and to identify amino acid residues with important structural and functional roles.
The Life Cycle of a Protein; Expressional Proteomics
The number of proteins produced by an individual is much larger than the number of genes encoded by that individual's genome. Moreover, the spectrum of expressed proteins (the proteome) varies in different cell types and tissues and in response to age, environmental factors, disease states, and therapies. This lecture examines some of the mechanisms by which the proteome is regulated and summarises the major approaches for proteome analysis.
More is Better: One Gene - Many Proteins
After proteins are produced at the ribosome they can undergo a wide variety of post-translational modifications, with profound influences on their functional properties. This lecture explores several of these modifications and their functional consequences.
What Do Inflammation, HIV, and Malaria Have in Common?
A critical aspect of inflammation is the migration of leukocytes (white blood cells) into the tissues. This migration is regulated by the activation of chemokine receptors in the leukocyte membranes. However, pathogens such as HIV and malaria can "hijack" natural chemokine receptors to gain entry into blood cells. Both the physiological and pathological functions of chemokine receptors are dependent on specific post-translational modifications of these receptors.
PART V: PROTEIN STRUCTURE AND FUNCTION
From Sequence to Structure: Protein Folding
The three-dimensional (3D) structures of proteins are essential for their function and activity. The 3D structure of a protein is defined by its amino acid sequence. This lecture will discuss how a protein gets to its native folded structure and how we describe and define protein structures.
From Sequence to Structure: Structure Determination
Knowledge of the 3D structure of a protein provides an understanding, at the atomic level, of how a protein functions, or as in the diseased state, how a protein malfunctions. This lecture will review the principles of protein structure, and give an overview of various methods involved in protein structure determination and analysis.
From Structure to Function: Binding Proteins
The biological functions of proteins are typically carried out though transient binding interactions with each other and with other molecules. This lecture, we will discuss the relationship between the strength of binding interactions and the structures of the molecules involved. The lecture will also present methods for observe and measure these interactions.
From Structure to Function: Enzymes
Enzymes are proteins that catalyse (speed up) biochemical reactions. They carry out this function by binding to the reaction substrates then binding more strongly to the transitions states of the reactions. Thus, enzyme interactions with their substrates represent a special case of the importance of binding interactions.
One Protein - Multiple Structures - Multiple Functions
Although we commonly think of proteins as having static structures, in reality they are constantly undergoing conformational fluctuations. Indeed some proteins have evolved to be able to interchange between different structural (and therefore different functional) states. We will examine a case in which a protein can undergo a large structural rearrangement between two forms with different functions.
Protein Machines: Creations of a Blind Watchmaker
Proteins are the molecular machines of our bodies. This lecture will present examples of proteins as molecular machines and present evidence for the ways they function.
Improving on Nature: Rational Design of Protein Therapeutic
The advent of biotechnology has made it possible to develop proteins as drugs. However, most natural proteins are not ideal as therapeutic agents because of properties such as low stability, aggregation, low bioavailability, or immunogenicity. In this lecture we will discuss cases in which bioactive proteins have been "engineered" to enhance their therapeutic properties.
Rational Design of Small Molecule Therapeutics
Traditional drug discovery relies on either serendipity or screening vast libraries of compounds for the identification of lead molecules. Recent advances in computational biology have allowed the development of rational drug design. Some of the basic principles of structure-based drug design will be described.
Web Sites for Disease Protein Assignment
This lecture will review features of the web sites that students will be preparing for the Disease Protein Assignment. Dr Kotsanas will provide guidance and answer questions about web site preparation, presentation and submission.
Navigating the Scientific Literature
- Methods to access scientific journals
- Use of PubMed to search the scientific literature
- Consolidation of concepts relating to translation and the genetic code
DNA Databases and Sequence Analysis
- Introduction to NCBI bioinformatics databases and tools
- Finding similar DNA sequences (BLASTn)
- Retrieving information about a gene
- Finding proteins encoded by DNA sequences (BLASTx)
- Finding Open Reading Frames (ORFs)
- Manipulating a DNA sequence
Exploring the Human Genome
- Finding a human gene (OMIM)
- Viewing and navigating genome maps
- Finding Expressed Sequence Tags (ESTs)
- Comparing genomes or humans and model organsims
Webpages - Design and Use
- Retrieve information from web on allocated biomedical topic and on your disease protein
- Construct a web site
Mining Protein Sequence Databases
- Haemoglobin as example for sequence retrieval
- Identify unknown protein; retrieve PDB file / identifier
Protein Families - Finding Members and Building Trees
- Make file of granzymes for multiple alignment
- Build simple tree for human granzymes
- Look at more complex tree using cytochrome C
Exploring Protein Architecture
- Carry out Pymol Tutorial
- Examine features of protein structure and stabilizing interactions
Protein Structural Comparisons
- Study chymotrypsin structure using Pymol
- Load and look at structure of disease protein
Protein Conformational Changes
- Compare different structural states of a protein
- Define changes in structure