comp 564:introduction to protein structure predictionjeromew/teaching/564/w... · comp...
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COMP 564:Introduction to protein structure
predictionJérôme Waldispühl
School of Computer ScienceMcGill University
Folding problemKLHGGPMLDSDQKFWRTPAALHQNEGFT
Nétats
~ 10n
n = 100-300
Levinthal paradox
Amino acids: The simple ones
Amino acids: Aliphatics
Amino acids: Cyclic and Sulfhydryl
Amino acids: Aromatics
Amino acids: Aliphatic hydroxyl
Amino acids: Carboxamides & Carboxylates
Amino acids: Basics
Histidine ionisation
Primary structureA peptide bond assemble two amino acids together:
A chain is obtained through the concatenation of several amino acids:
Peptide bond is pH dependent
Peptide bonds lies on a plane
Bond lengths
Peptide bond features (1)
Peptide bond features (2)
The chain has 2 degrees of liberty given by the dihedral angles F and Y.The geometry of the chain can be characterized though F and Y.
Peptide bond features (3)
Cis/trans isomers of the peptide group
Trans configuration ispreferred versus Cis(ratio ~1000:1)
An exception is theProline with a preferenceratio of ~3:1
Ramachandran diagram gives the values which canbe adopted by F and Y
CαH
N C
H O
ψ
φ
CH2
NH3
CH2
CH2
CH2
+
Lysine
χ1
χ2
χ3
The side chains also have flexible torsion angles
-2.5
-4.3
The preferred side-chains conformationsare called “rotamers”
Example: Asparagine-3.3
Typical conformations experimentally observedconformations observed by simulation
Energy (chi1,chi2)
Cα NCCβ
Cγ
OδN
δ
χ1
χ2
-4.5
chi2
chi1
1 kcal/mole betw
een levels
α helix β−sheet
In helices and sheets, polar groups are involved intohydrogen bonds
3.6 residuesper turn
Pseudo-periodicity of 2
a-helix
3.6 residues per turn, H-bond between residue n and n+4Although other (rare) helices are observed: p-helices, 3.10-helices...
b-sheets
b-strand (elementary blocks) :
b-strands are assembled into(parallel, anti-parallel)b-sheets.
b-sheets
Anti-parallel b-sheets
Parallel b-sheets
b-sheetsVarious shapes of b structures
Twisted b-sheets b-barrel
b-sheets
Loops
turn
~ 1/3 of amino acids
Loops
Super-secondary & Tertiary structure
The tertiary structure is the set of3D coordinates of atoms of a singleamino acid chain
Secondary structure elementscan be assembled intosuper-secondary motifs.
Quaternary structure
A protein can be composedof multiple chains withinteracting subunits.
Protein can interact with moleculesExample: Hemoglobin
An Heme (iron + organic ring) binds to the protein, andallow the capture of oxygen atoms.
Disulfide bond
Two cysteines can interactand create a disulfide bond.
Cytochrom cHemoglobine
water
The tertiary structure is globular, with a preferencefor polar residues on its surface but rather apolar in
its interior
Membrane proteins are an exception
~ 30% of human genome, ~ 50% of antibiotics
Cytochrom oxidase
lipidProtein
Lipid bilayer
Hydrophobiccore
Hydrophilicregion
Proteins folds into a native structure
Overview of the methods used to predictthe protein structure
● Which degree of definition?● What's the length of the sequence?● Which representation/modeling suits the best?● Should we simulate the folding or predict the structure?● Do we want a single prediction or a set of candidates?● Machine learning approach or physical model?
Several issue must be addressed first:
Molecular Dynamics
HP lattice model
Hidden Markov models(and other machine learning approaches)
Structural template methods