L19 Bioinformatics II - Protein structure prediction

what is primary structure

amino acid sequence

what is secondary structure

local confirmation of stretches of sequence

what is tertiary structure

3D confirmation of one polypeptide chain

what is quaternary structure

aggregation of two or more polypeptide chains

what is the primary structure held together by

a peptide bond (COOH of amino acid 1 to NH2 of amino acid 2)

what can primary structure be predicted from

the genome sequence

how can the primary structure be predicted

• gene prediction

• in silico translation

what amino acids have higher tendencies to form alpha-helix structures

M, A, L, E and K

what amino acids are helix breakers

G and P

what are the 2 main classes of secondary structure

• alpha helix

• beta sheet

what accuracy can the secondary structure be predicted from the primary structure

80-90%

what are local secondary structures held together with

hydrogen bonds

what does tertiary structure prediction rely on

solved structures

tertiary structure is … complex

thermodynamically

what are copies of the same proteins called

homomers

what are copies of different proteins called

heteromers

what can quaternary structure be

• homomers

• heteromers

give an example of a heterotetramer

functional haemoglobin A

how many entries does UniProt have

100s of millions

how many entries does PDB+ have

100s of thousands

when was the first method of predicting secondary structure

50 years ago

how accurate are modern algorithms of secondary structure

>80% (e.g PSIPRED)

what do modern algorithms use for secondary structure

information from alignments to inform prediction

what can multiple secondary structure alignments be made using

an iterative BLAST search

what do secondary structure predictions extract information using

machine learning

what is machine learning

• an artificial neural network that has been trained on known secondary structure

• each amino acid in the primary structure is given 1 of 3 states (helix, sheet or coil)

what are the two main approaches in predicting tertiary structure

• template based modelling

• ab initio modelling

what are the advantages of using a template for predicting tertiary structure

• more straight-forward

• less computationally expensive

what are the disadvantages of using a template for predicting tertiary structure

relies on a similar protein having had its structure determined

give an example of an algorithm for tertiary structure

iTASSER

what is the assessment of prediction quality

general accuracy of structure prediction methods determined by comparison to known structure

how has the assessment of prediction quality been done

systematically since 1990s by an international competition

• critical assessment of structure prediction (CASP)

• every 2 years since 1994

what is the Global Distance Test used to do

devise multiple metrics for assessing model quality

how does the Global distance test work

• all segments of 3,5 and 7 consecutive amino acids from the model are superimposed to the actual structure

• each of them will be iteratively extended while they are good enough

what is ‘good enough’ in the global distance test

distance between all residue pairs (represented by their Calpha atoms) is less than a threshold

what is ‘GDT’ in the global distance test

number of amino acids in segments/total number of amino acids in a protein

what is the global distance test - total score (GDT-TS) an average of

GDT with thresholds of 1,2,4 and 8 Angstroms

what is AlphaFold

a protein structure prediction method developed by DeepMind (Google)

what does AlphaFold start with

protein multiple alignment

what does AlphaFold use to learn to predict structure

sophisticated AI