Structure and stability of globular proteins. Aliphatic amino acids and Gly. Cyclic Imino Acid: Proline. Hydroxyl amino acids. Acidic amino acids. Amide amino acids. Basic amino acids. Histidine. Sulfur-containing amino acids. Aromatic amino acids.
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Picture from T. Przytycka, 2002
Assumption: amino acid sequence completely and uniquely determines the protein tertiary structure.
Protein folding problem: find native conformation among the large number of alternative conformations.
Ex: polypeptide chain of 100 residues can have ~ 9^100 different conformations.
Scale of interactions in proteins:
- Interactions less than kT~0.6 kcal/mol
- ΔG ~ 5 - 20 kcal/mol
Potential energy = Van der Waals + Electrostatic + …
Coulomb’s law for two point charges in a vacuum:
q – point charge,
ε – dielectric constant
ε = 2-3 inside the protein,
ε = 80 in water
d = 2.76 Å,
E = 120 kcal/mol
Interaction energy of two dipoles separated by the vector r:
μ = 3.5D,
μ = 1.85D.
Distance between centers of atoms
Three major types of interactions:
1. Most HB are local, close in sequence.
2. Most HB are between backbone atoms.
3. Most HB are within single elements of secondary structure.
4. Proteins are almost equally saturated by HB: 0.75 bond per amino acid.
PROTEIN + GS-SG PROTEIN + GSHPROTEIN + 2GSH
- Breakdown and formation of S-S bonds are catalyzed by disulfide isomerase.
- In the cell S-S bonds are reversible, the energetic equilibrium is close to zero.
- Secreted proteins have a lot of S-S bonds since outside the cell the equilibrium is shifted towards their formation.
HB determines properties of water:
- tetrahedral structure of ice, 4 HB neighbors,
very open lattice.
- liquid water forms HBonded “icebergs”.
Unusual physical properties:
- water expands when it freezes at 0 C. When ice is melted and then warmed, the liquid continues to contract upto 4C.
- water has high melting and boiling points, large heat capacity.
Hydrophobic interaction – tendency of
nonpolar compounds to transfer from an
aqueous solution to an organic phase.
Disordered globule: hydrophobic – inside, hydrophilic - outside
Native highly ordered conformation
Picture from Branden & Tooze “Introduction to protein structure”
Adjacent antiparallel β-strands are joined by hairpin loops.
Loops are more flexible than helices and strands.
Loops can carry binding and active sites, functionally important sites.
Branden & Tooze “Introduction to protein structure”
in 2002 – 17000 structures including NMR structures
Exceptions: short identical amino acid sequences can sometimes be found in different SS.
Accuracy: 65% - 75%, the highest accuracy – prediction of an α helix
Amino acid itself determines the type of secondary structure, which it is likely to adopt.
Analysis of frequences for all amino acids to be in different types of SS.
Ala, Glu, Leu and Met – strong predictors of alpha-helices,
Pro and Gly predict to break the helix.
Prediction of an alpha-helix - if four of six adjacent amino acids have high probability to be a helix.
Prediction of a beta-strand – if three of five adjacent amino acids have high probability to be a strand.
Assumption:formation of SS of an amino acid is determined by the neighboring residues (usually a window of 17 residues is used).
GOR uses principles of information theory for predictions.
Method maximizes the information difference between two competing hypotheses: that residue “a” is in structure “S”, and that “a” is not in conformation “S”.
Input sequence window