Primary through quaternary protein structure; folds, domains, folding pathways, chaperones, PTMs.
Protein Structure
Primary structure
Linear sequence of amino acids joined by peptide bonds, numbered from N- to C-terminus. Sequence alone (Anfinsen 1961) encodes the folded…
Secondary structure
Local backbone conformation stabilised by hydrogen bonds between amide N-H and carbonyl C=O groups. Canonical elements: α-helix, β-sheet,…
α-helix
Right-handed spiral with 3.6 residues per turn, 1.5 Å rise per residue, i→i+4 H-bonds. Pauling-Corey-Branson 1951 — predicted before…
β-sheet
Extended backbone conformation with inter-strand H-bonds; parallel or antiparallel. Side chains alternate above/below the sheet plane.
Ramachandran plot
φ (N-Cα) vs ψ (Cα-C) dihedral angle scatter for protein residues; allowed regions cluster around α-helix (-60,-45), β-sheet (-120,120),…
Hydrophobic effect
Entropically-driven clustering of nonpolar side chains away from water; dominant force collapsing polypeptides into compact folds (Kauzmann…
Tertiary structure
3D fold of a single polypeptide chain — packing of secondary-structure elements into domains stabilised by hydrophobic core, H-bonds, salt…
Quaternary structure
Assembly of multiple subunits (homo- or heteromeric) into a functional complex. Examples: haemoglobin α2β2, ATP synthase, ribosome, 20S…
Protein folding
Kinetic+thermodynamic process by which a polypeptide reaches its native fold. Levinthal's paradox resolved by funnel-shaped energy…
Anfinsen's dogma
Native fold of a small globular protein is determined entirely by its primary sequence under physiological conditions (ribonuclease A…
Molecular chaperone
Protein that assists folding of other proteins without being part of the final structure. Major families: Hsp70 (DnaK), Hsp90, chaperonins…
Hsp70 chaperone
ATP-dependent chaperone that binds exposed hydrophobic segments on nascent/misfolded chains. Works with J-domain co-chaperones (Hsp40/DnaJ)…
Hsp90 chaperone
ATP-dependent dimer chaperone that matures signalling clients (kinases, steroid receptors). Drug target in oncology (geldanamycin, 17-AAG).
GroEL-GroES chaperonin
Bacterial chaperonin: GroEL (14-mer double ring) + GroES (7-mer lid) sequester misfolded substrate in a hydrophilic Anfinsen cage for…
Intrinsically disordered protein
Protein or region lacking stable tertiary structure under native conditions, often rich in charged/polar residues. Involved in signalling…
Protein domain
Compact, independently folding unit of ~50-250 residues with conserved sequence and structure. SCOP/CATH classify ~1400 folds;…
Post-translational modification
Covalent modification of residues after translation: phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, glycosylation,…
Phosphorylation
Reversible addition of a phosphate group to Ser/Thr/Tyr (eukaryotes) or His/Asp (two-component). Regulates ~30% of eukaryotic proteome;…
Ubiquitination
Covalent attachment of 76-residue ubiquitin via isopeptide bond to Lys side chain. K48 polyubiquitin targets proteasomal degradation; K63…
Glycosylation
Attachment of oligosaccharide chains to Asn (N-linked, Sec61-translocon) or Ser/Thr (O-linked). Occurs in ER/Golgi; regulates folding,…
Ramachandran plot (1963)
G N Ramachandran 1963 phi-psi plot; modern hot-spots + outlier-detection in structure validation.
Alpha-helix beta-sheet (Pauling 1951)
Pauling-Corey 1951 (Nobel 1954) alpha-helix + beta-sheet; H-bond + dihedral; foundational.
Anfinsen (1961)
C Anfinsen 1961 (Nobel 1972) sequence determines structure; thermodynamic-hypothesis + Levinthal paradox.
Levinthal paradox (1969)
C Levinthal 1969 protein-folding paradox; modern funnel-landscape + nucleation-condensation resolution.
Chaperones (Ellis 1991)
R J Ellis 1991 + Hartl 1996 molecular-chaperones HSP60 + HSP70 + HSP90; modern proteostasis network.
AlphaFold-2 (2021)
DeepMind 2021 ~1A median accuracy; modern AF3 multi-modal 2024; revolutionized structural biology.