Computational Molecular Microbiology (MBIO 4700) Lecture Notes PDF

Computational Molecular Microbiology (MBIO 4700) ABDULLAH ZUBAER UNIVERSITY OF MANITOBA Protein structure validation programs ▪ PROCHECK ▪ ERRAT ▪ Rampage ▪ WHATIF ▪ ProQ ▪ SuperPose https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102779 Molecular docking simulation ▪ Molec...

Computational Molecular Microbiology (MBIO 4700) ABDULLAH ZUBAER UNIVERSITY OF MANITOBA Protein structure validation programs ▪ PROCHECK ▪ ERRAT ▪ Rampage ▪ WHATIF ▪ ProQ ▪ SuperPose https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102779 Molecular docking simulation ▪ Molecular docking is an important component of the drug discovery process ▪ Modeling the interaction between a small molecule and a protein ▪ Efficiency can be improved if binding pockets are known ▪ Ligand-protein complex https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151162/ https://en.wikipedia.org/wiki/Docking_(molecular) Docking programs ▪ Autodock ▪ Autodock Vina ▪ Ligand databases: ▪ PubChem ▪ DrugBank ▪ ZINC etc. Protein-Protein interaction (PPI) • Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and the hydrophobic effect. • Protein-protein interaction plays key role in predicting the protein function of target protein and drug ability of molecules. The majority of genes and proteins realize resulting phenotype functions as a set of interactions. • Many are physical contacts with molecular associations between chains that occur in a cell or in a living organism in a specific biomolecular context. • The Human Reference Interactome (HuRI) map charts 52,569 interactions between 8,275 human proteins https://news.harvard.edu/gazette/story/2020/04/scientists-produce-a-reference-map-of-human-protein-interactions/ Regulation or protein-protein interactions • Protein concentration, which in turn are affected by expression levels and degradation rates • Protein affinity for proteins or other binding ligands • Ligands concentrations (substrates, ions, etc.) • Presence of other proteins, nucleic acids, and ions • Electric fields around proteins • Occurrence of covalent modifications https://en.wikipedia.org/wiki/Protein%E2%80%93protein_interaction Types of cellular functions regulated by protein-protein interactions Electron transfer proteins: In many metabolic reactions, a protein that acts as an electron carrier binds to an enzyme that acts its reductase. After it receives an electron, it dissociates and then binds to the next enzyme that acts its oxidase (i.e. an acceptor of the electron). Signal transduction: Signal propagation inside and/or along the interior of cells depends on PPIs between the various signaling molecules. Types of cellular functions regulated by protein-protein interactions Cell metabolism: In many biosynthetic process enzymes interact with each other to produce small compounds or other macromolecules. Muscle contraction: Physiology of muscle contraction involves several interactions. Myosin filaments act as molecular motors and by binding to actin enables filament sliding. Membrane transport: A protein may be carrying another protein. Online tools for Protein-protein interaction analysis (STRING) https://string-db.org/ Online tools for Protein-protein interaction analysis (STRING) http://viruses.string-db.org/ Central Dogma of Biology DNA What can happen? RNA What appears to be happening Environmental Factors Proteins Metabolites What makes it happen What has happened or is in process Human Health and Disease Functional analysis Functional analysis methods help us to gain insight about the biology underlying a list of genes. These genes could be output from a differential expression analysis. Gene Ontology (GO) • An ontology is a formal representation of a body of knowledge within a given domain. Ontologies usually consist of a set of classes (or terms or concepts) with relations that operate between them. • The Gene Ontology (GO) describes knowledge of three aspects of the biology of the gene/protein: What type of data can be analysed? Differentially expressed Genes ◦ RNAseq Analysis, RNA Microarray Differentially expressed Proteins ◦ E.g. Mass spectrometry, SOMAScan data, Protein Microarray What type of questions can be answered? What is the impact of a viral infection of a cell? What is the impact of a drug treatment/ stress/ protein knockdown? Function of the differentially expressed genes/ proteins in a disease condition. Signaling pathways affected by a disease/ stress or viral infection. What are the location of the differentially dysregulated proteins in the cells? Platform for Functional analysis DAVID (https://david.ncifcrf.gov/) PANTHER (http://pantherdb.org/) reactome (https://reactome.org/) REVIGO (http://revigo.irb.hr/) G-Profiler (https://biit.cs.ut.ee/gprofiler/gost) Enrichr (https://maayanlab.cloud/Enrichr/) Database for Annotation, Visualization and Integrated Discovery (DAVID) (https://david.ncifcrf.gov/) DAVID Analysis Copy protein names from dataset DAVID Analysis reactome (https://reactome.org/) Reactome Analysis