Protein Structure

Amino acids are chiral about carbon-2, and the ones used by cells are the L-isomers.


Backbone Flexibility and Conformations:


The peptide bond has partial double bond character, which means there is no rotation.

  • All atoms bonds connected are coplanar (in the same plane).


Torsional Flexibility:

  • Two dihedral angles confer torsional freedom.

  • Φ - N-side peptide bond-Cα-CO

  • Ψ - N-Cα-CO-peptide bond.


The lone pair on the nitrogen atom delocalises into the adjacent carbonyl. This provides the double-bond character which prevents free rotation about the peptide bond and therefore favours a planar geometry.


Secondary Structure of Proteins:


Secondary Structure is the local conformation of the polypeptide chain, which forms spontaneously at the ribosome immediately after translation.

  • It is stabilised by hydrogen bonds between backbone N-H and C-O.

    • Contains alpha helices, beta sheets and beta turns.


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Ramachandran Plots:


They are a plot of restricted set of allowed Φ and Ψ combinations and backbone combinations.

  • They show the energy landscape for conformational selection.

  • Plots individual Ψ and Φ pairs for each amino acid residue.

  • Shows secondary structure content.


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Alpha Helices:


Alpha helices have a hydrogen bond between i and i+4.

  • They have an angular increment of 100 degrees per residue, a helical pitch of 5.4Å, and 3.6 residues per helical turn.

    • They have an average length of 10 residues.


Helical wheels visualise the orientation of side chains in helices.

  • Sidechains are directed outwards and away from the helix.

    • 18 residues advance 5 full turns.


Helical formation is preferentially right-handed.


❗ 310-helices have i, i+3 hydrogen bonding, and π-helices have i, i+5 hydrogen bonding.


A key example of helical proteins is the human beta-adrenoreceptor.


β-Pleated Sheets:


The chain is extended instead of coiled.

  • Extended chains can run antiparallel or parallel in consecutive strands to form sheets.

    • The structure is stabilised by hydrogen bonds between HN and OC from opposite strands.

      • Sidechains point out of the plane on the sheet.


Twisted sheets are a variant of the beta-pleated sheet.

  • Omega loops and reverse turns are important secondary structural elements that allow for changes in direction within the polypeptide chain.

    • Omega loops are relatively long, often containing 5 to 15 residues, connecting two secondary structures with greater flexibility.

    • Reverse turns are shorter structures that usually occur at the surface of proteins, allowing the polypeptide to reverse direction and are essential in protein folding.

Super-Secondary Structure:


Super-secondary structure in proteins refers to structural motifs that involve the combination and arrangement of elements from secondary structures such as alpha helices and beta sheets.

  • Common examples include motifs like beta-alpha-beta and alpha-alpha corner.

  • One type is molten globules, which are partially folded, intermediate states of a protein with unique structural properties.


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Structural Motifs:


  • “EF Hand” - Ca2+ binding motif from calmodulin.

  • Zinc Finger motif - involved in DNA binding.

  • Leucine Zipper - involved in DNA binding as transcription regulators.

  • Rossmann Fold - β-α-β-α-β - e.g. enzymes, dehydrogenases.

  • Virulence-associated proteins.


Tertiary Structure:


Tertiary structure describes the folded final 3D state of a protein.

  • Contains secondary structure elements, and larger structural motifs.

  • The final conformation can be stabilised by non-covalent interactions.

    • Hydrophobic interactions drive folding.

    • Electrostatic interactions (salt bridges and charge-charge).

    • Hydrogen bonds.

    • Van der Waals interactions.

  • Also by post-translational covalent modifications

    • E.g. disulfide bonds, thioether bonds etc.