Bonev - Protein structure prediction Flashcards
In bioinformatics, FASTA is used. What is this?
Where the amino acid residues are ordered from a sequence, each being denoted in their singular letter form
What does BLAST do?
Allows similarity between sequences being compared to known sequences
How is an alignment score determined?
Calculation of the probability of finding a pair of amino acids normalised to the probability of random occurrence. The higher the number, the better the alignment.
If we know the primary structure, what two methods can be used to determine how the protein fold?
Ab initio protein structure predicition and Template-Based homology Modelling (TBM)
What is TBM?
Sequence alignment with proteins which are already structurally understood, meaning we can determine already known sequences for folds
How can we work out the secondary structure from the sequence?
Residues in the sequence typically either form an alpha helix or beta sheet
Alpha helix = four out of six residues start a helix - continue in each direction until four helix-breakers
Helix-formers = Glu, Ala, Leu
Helix-breakers = Asn, Tyr, Pro, Gly
Beta sheet = three out of five formers - six breakers
Beta-formers = Met, Val, Ile, Asp
Beta-breakers = Glu, His, Lys, Ser, Asn, Pro
What are the first two stages in Homology Remodelling?
- Start with the linear sequence of the protein (FASTA)
- Identify suitable templates (BLAST search)
What are the next two steps?
- Choose homologous residues and atoms
- Align segments between structural template and our own sequence
Then fill the gaps using first principle folding rules and then use a virtual ribosome
RMSD stands for Root Mean Square Deviation, and it is a measure of the average distance between the atoms of two protein structures. Minimizing RMSD during TBM is important because it reflects the accuracy and quality of the predicted model. A lower RMSD indicates a higher degree of similarity between the predicted model and the experimental structure, suggesting a more accurate prediction. Minimizing RMSD helps ensure that the predicted model captures the essential features of the target protein’s structure, such as its overall fold, secondary structure elements, and key functional regions.
What are the two ways of identifying possible targets and ligands for drug use?
Target-based or ligand-based approaches
What is the target-based method?
A target-based approach in drug screening focuses on identifying and validating a specific protein involved in a disease process. Compounds are then screened and optimized to interact with this target, leading to the development of potential therapeutics. Identify candidate protein from genome and undergo Structure Based Virtual Screening (SBVS).
What is the ligand-based method?
Start with the identification of a known active ligand, which is a compound that binds to a target molecule and exhibits the desired biological activity. This active ligand serves as a reference for subsequent steps in the drug discovery process. LBVS.
What is molecular docking?
Molecular docking is a computational technique used in drug discovery and molecular modeling to predict how a small molecule (ligand) interacts with a target protein or receptor. It aims to predict the most favorable binding orientation and conformation of the ligand within the binding site of the target molecule. A ligand may have a change in ∆G and this indicates a stable ligand-recptor complex.
