Unit 7: Structural and Computational Biology — Interactive Notes
Definition: Structural biology deals with the study of three-dimensional (3D) structures of macromolecules (including proteins and nucleic acids) at atomic levels.
Importance: It provides detailed information about the structure of a biomolecule, its functions, dynamics and interaction with ligands and other macromolecules.
Structural biologists determine 3D structures of macromolecules, revealing the exact location, shape, and environment of active sites and domains (distinct structural units with independent functions).
Significance: Knowing the location and structure of these domains has helped design antiviral drugs that specifically target them. Similarly, the structure of serine proteases reveals its well-defined active site, responsible for breaking down peptide bonds.
Structural biology helps scientists find the right place on a disease-causing molecule (usually a protein, called a drug target) where a drug can work. E.g., in COVID-19, scientists studied the SARS-CoV-2 spike protein (helps virus enter human cells), identified it as a drug target, and designed vaccines/medicines that block it.
By studying 3D structures of both pathogen and host cell proteins, scientists can see how the pathogen attaches to and enters the host cell. E.g., studying the coronavirus spike protein and the human ACE2 receptor revealed exactly how the virus enters human cells — vital for developing drugs that bind receptor proteins, inhibiting viral entry.
Protein functionality depends on correct 3D folding. Several diseases (cystic fibrosis, Parkinson's, Alzheimer's) originate due to incorrect protein folding. Structural biology helps understand folding pathways and how misfolding leads to disease.
Discovery: Developed in 1912 by William Henry Bragg and William Lawrence Bragg — awarded the 1915 Nobel Prize in Physics. Used to analyse minerals, salts, metals, proteins, carbohydrates, nucleic acids and vitamins.
Principle: X-ray beams strike crystal atoms; molecules in the crystal diffract the beam in specific directions. From the angles/intensities of diffracted beams, a 3D picture of electron density within the crystal is produced — exploited to create the 3D structure of the molecule.
(i) Protein Crystallization: turning purified protein into a solid crystal form (regular repeating pattern needed for a clear image). Achieved by slowly mixing protein with special solutions — can take hours to weeks, needs careful control of temperature, pH, salt concentration.
(ii) Production of a diffraction pattern: the crystal is mounted on the X-ray machine; X-rays bombarded at various angles; atoms diffract the beam, creating a diffraction pattern (series of spots) on detectors.
(iii) Creating density map: the angles/intensities of the spots contain information about atom arrangement, used to make a density map.
(iv) Determination of protein structure: data is analyzed mathematically using computational programs, transforming it into the 3D structure of the protein.
Definition: Computational biology is an interdisciplinary field using computational techniques and tools to solve biological problems, integrating biology, computer science, mathematics and statistics.
Importance: handles large datasets, uncovers hidden patterns, generates predictive models leading to new biological insights.
(i) Genomics: the study of genomes (complete DNA set within a cell) — sequencing, assembling, analyzing genome function/structure; helps understand genetic variations, gene function, evolutionary relationships.
(ii) Proteomics: large-scale study of proteins, their structures and functions — maps the entire proteome and understands interactions/roles in cellular processes.
(iii) Bioinformatics: application of computer technology to manage/analyze biological data — tools to store, retrieve, analyze DNA, RNA and protein sequences.
(i) Drug Discovery: identifies potential drug targets, simulates drug effects, predicts drug-protein interactions.
(ii) Genetic Research: identifies genetic variations associated with diseases, aids personalized medicine.
(iii) Evolutionary Biology: compares genetic information across species to reconstruct evolutionary relationships.
Databases: organized collections of biological data, including genetic sequences, metabolic pathways, protein structure and other related information.
1. GenBank: a comprehensive public database of nucleotide sequences and supporting bibliographic/biological annotations — provides access to a vast repository of DNA sequences, facilitating genetic research and comparative genomics.
2. Protein Data Bank (PDB): provides 3D structural data of large biological molecules (proteins, nucleic acids) — important for studying macromolecule structures, understanding functions, and designing drugs.
3. Ensembl: a genome browser providing genome sequences, gene models, and comparative genomics for various species — helps access/visualize genomic data for genomics and evolutionary biology studies.
Algorithms: a systematic, step-by-step computational procedure or set of rules designed to solve specific biological problems or analyze data.
1. BLAST (Basic Local Alignment Search Tool): compares primary biological sequence information (amino acid or DNA nucleotide sequences) — helps identify homologous sequences, predict functions of unknown genes, and study evolutionary relationships.
2. FASTA: a sequence alignment tool comparing a query sequence to a database of sequences to find regions of similarity — used for searching protein/nucleotide databases, identifying sequence homology, and analyzing sequence alignments.
Sequence homology: similarity between DNA, RNA, or protein sequences due to shared ancestry.
Categories: Orthologs — sequences in different species from a common ancestral gene via speciation, often retaining the same function. Paralogs — sequences within the same species from gene duplication, which can evolve new functions.
• Insight into evolutionary relationships between organisms.
• Infers evolutionary history and divergence of species.
• Clue about the function of an unknown gene/protein.
• Understanding disease mechanisms across species, developing treatments.
• Homologous genes in model organisms give insights into human diseases.
Structural Homology: similarity in the 3D structures of proteins or other macromolecules due to shared ancestry. Proteins with similar structures often perform similar functions, even if their sequences are not highly similar.
• The 3D structure of a protein provides critical information about its function.
• Helps predict the function of newly discovered proteins.
• Crucial in drug designing — drugs are designed to interact with specific protein structures.
• Helps design more effective drugs by understanding structural relationships between proteins.
• Helps understand evolutionary processes shaping protein functions and interactions.
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