Proteins - Three Dimensional Structure

Flashcards covering key concepts related to protein three-dimensional structure, including primary, secondary, tertiary, and quaternary structures, stability, folding mechanisms, and associated diseases from the lecture notes.

What is the primary structure of a protein?

The linear sequence of amino acids in a polypeptide chain.

How is secondary protein structure defined?

The local spatial arrangement of a polypeptide's backbone atoms, without considering side chain conformations.

What does tertiary protein structure describe?

The three-dimensional structure of an entire polypeptide, including its side chains.

What is the definition of quaternary protein structure?

The spatial arrangement of a protein's subunits (multiple polypeptide chains).

Why does the peptide group have a rigid, planar structure?

Due to resonance interactions that give the peptide bond approximately 40% double-bond character.

Which conformation do peptide groups typically assume, and why?

The trans conformation, because the cis conformation is less stable due to steric interference, except for ~10% of Pro residues.

What are the two torsion angles that describe the conformation of a polypeptide backbone?

Phi (φ) around the Cα-N bond and Psi (ψ) around the Cα-C bond.

What is a Ramachandran diagram used for?

To summarize the sterically allowed values of the φ and ψ torsion angles for amino acid residues in a polypeptide.

Which amino acid residue has a limited range of φ values, and what is its typical angle?

Proline (Pro), limited to angles around -60°.

Which amino acid residue is less sterically hindered and covers a greater area on a Ramachandran diagram?

Glycine (Gly), because it is the only residue without a Cβ atom.

What are the two most common types of regular secondary structures in proteins?

The α helix and the β sheet.

What is the hydrogen bonding pattern in an α helix?

The peptide C=O bond of the nth residue points along the helix axis toward the peptide N-H group of the (n+4)th residue.

Describe the handedness, residues per turn, and pitch of a standard α helix.

It is right-handed, has 3.6 residues per turn, and a pitch of 5.4 Å.

How do β sheets differ from α helices in their hydrogen bonding?

In β sheets, hydrogen bonding occurs between neighboring polypeptide chains, rather than within a single chain.

What are the two varieties of β sheets?

The antiparallel sheet (neighboring chains run in opposite directions) and the parallel sheet (chains extend in the same direction).

Which type of β sheet is less stable?

Parallel β sheets are less stable than antiparallel β sheets.

What are reverse turns or bends, and where do they typically occur?

Short stretches of polypeptide that abruptly change direction, often occurring at protein surfaces and involving four successive amino acid residues.

What is the primary component of α-keratin, and how is it structured?

A coiled coil structure formed by two α-helical polypeptides twisting around each other to form a left-handed coil.

What characteristic of α-keratin influences whether it is 'hard' or 'soft'?

It is rich in Cys residues, and its sulfur content determines its 'hardness' or 'softness'.

Describe the unique structure of collagen.

A triple helix formed by three polypeptide chains winding around each other with a gentle, right-handed, ropelike twist.

What is the distinctive amino acid composition of collagen?

Approximately one-third Glycine, 15 to 30% Proline, and significant amounts of 4-hydroxyprolyl (Hyp), 3-hydroxyprolyl, and 5-hydroxylysyl (Hyl).

What is the significance of Glycine at every third position in collagen?

Due to tight packing in the triple helix, Glycine is absolutely required at every third position because its small side chain allows for close contact and hydrogen bonding between chains.

What technique is used to directly image molecules in a crystal to determine protein tertiary structure?

X-Ray crystallography.

What is a key difference between protein crystals and those of small molecules?

Protein crystals are highly hydrated, typically 40 to 60% water by volume.

What technique allows the determination of three-dimensional structures of globular proteins in aqueous solution?

Nuclear Magnetic Resonance (NMR) spectroscopy, specifically two-dimensional (2D) NMR techniques like COSY and NOESY.

When is cryo-electron microscopy (cryo-EM) particularly useful for determining macromolecular structures?

For fragile or flexible complexes that are difficult to crystallize and too large to visualize by NMR methods.

Where are nonpolar amino acid residues typically located in globular proteins?

Mostly in the interior of a protein, out of contact with the aqueous solvent.

Where are charged polar amino acid residues usually found in globular proteins?

Usually located on the surface of a protein in contact with the aqueous solvent.

What are 'motifs' or 'supersecondary structures' in proteins?

Specific groupings of secondary structural elements, such as the β-α-β motif, β hairpin motif, α-α motif, or Greek key motif.

Proteins can be classified into what three main categories based on their secondary structure content?

α proteins (mostly α helices), β proteins (mostly β sheets), and α/β proteins (mixtures of both).

What are protein 'domains'?

Globular clusters within larger polypeptides (>~200 residues) that are often structurally independent units and may have specific functions.

What is bioinformatics, specifically structural bioinformatics?

Bioinformatics is a discipline dealing with molecular sequences and structures; structural bioinformatics is concerned with displaying and comparing macromolecular structures.

What is the Protein Data Bank (PDB)?

The repository for structural information on macromolecules, containing coordinates for thousands of structures, each assigned a unique four-character identifier.

What is the quaternary structure of a protein?

The spatial arrangement of multiple polypeptide chains (subunits) in a multi-subunit protein.

What are the main advantages for proteins to exist as multi-subunit complexes (oligomers)?

Defects can be repaired by replacing a flawed subunit, and increasing protein size helps fix the three-dimensional positions of reacting groups, which can enhance enzymatic activity.

What types of symmetry can proteins typically have in their quaternary structure?

Only rotational symmetry, including cyclic symmetry, dihedral symmetry, and the symmetries of a tetrahedron, cube, and icosahedron.

What is the major determinant of native protein structure and stability?

The hydrophobic effect, which drives nonpolar residues to the interior of the protein away from the aqueous solvent.

Do hydrogen bonds and ion pairs contribute significantly to the overall stability of a native protein?

No, while they are central features of protein structures, they make only minor contributions to the overall stability of a native protein.

What type of bonds are important for 'locking in' a particular backbone folding pattern in extracellular proteins?

Disulfide bonds (covalent S-S cross-links).

Why are disulfide bonds rare in intracellular proteins?

Because the cytoplasm is a reducing environment, which prevents the formation or stability of disulfide bonds.

How can metal ions contribute to protein stability?

They can internally cross-link proteins, allowing relatively short stretches of polypeptide chain to fold into stable units, as seen in zinc fingers.

What are some conditions or substances that can cause protein denaturation?

Heating, pH variations, detergents, and chaotropic agents like guanidinium ion and urea.

What does the reversible renaturation of proteins like RNase A demonstrate?

It demonstrates that a protein can refold spontaneously into its native conformation under physiological conditions, implying that the protein's primary structure dictates its three-dimensional structure.

What are 'intrinsically disordered proteins'?

Proteins that contain segments (>30 residues) that are intrinsically unfolded in solution, rich in certain polar and charged amino acids, and often participate in signaling and regulation.

What is the driving force in protein folding, especially in the early stages?

What has been termed 'hydrophobic collapse,' leading to a molten globule state.

What is the 'molten globule' state?

A collapsed state during protein folding that has much of the secondary structure of the native protein but little of its tertiary structure.

What is the role of Protein Disulfide Isomerase (PDI) in protein folding?

PDI catalyzes the correct formation and rearrangement of disulfide bonds during protein folding, preventing the formation of non-native disulfide bonds.

What are 'molecular chaperones'?

Essential proteins that bind to unfolded and partially folded polypeptide chains to prevent improper association of hydrophobic segments, which could lead to non-native folding, aggregation, and precipitation.

Name two common classes of molecular chaperones.

Hsp70 (often with Hsp40), Trigger factor, Chaperonins (like GroEL/ES), and Hsp90.

What is the primary energy source for most molecular chaperones to facilitate protein folding?

ATP hydrolysis, as most chaperones are ATPases.

How do chaperonins like GroEL/ES facilitate protein refolding?

They bind improperly folded proteins and induce them to refold inside an internal cavity, driven by ATP binding and hydrolysis, which causes conformational changes.

What are 'amyloidoses'?

Human diseases associated with the extracellular deposition of normally soluble proteins in certain tissues, forming insoluble fibrous aggregates known as amyloids.

What protein accumulates in the brain tissue of individuals with Alzheimer's disease, forming amyloid plaques?

Amyloid-β protein (Aβ).

What type of protein is responsible for 'prion diseases' like Creutzfeldt–Jakob disease (CJD)?

A misfolded protein called a prion (PrP), which induces normal PrP proteins to adopt the altered, disease-causing conformation.

What protein accumulates into amyloid inclusions called Lewy bodies in Parkinson's disease?

α-synuclein.