Proteins I

What are the most abundant biological macromolecules

Proteins

What are the three protein shapes?

The three primary protein shapes are globular, fibrous, and membrane proteins.

Fibrous proteins?

• long, rod-like

• water insoluble

• Primary structural roles

Globular proteins

• compact, roughly spherical

• water-soluble

• enzymes, transport, regulation

Membrane proteins

• embedded in lipid bilayers

• contain amphipathic regions

• channels, receptors, signaling

4 levels of protein structure

Primary (linear amino acid sequence):

• Determined by gene sequence

Secondary (α-helices and β-sheets):

• Stabilized by backbone H-bonds

Tertiary (3D folding of single peptide):

• Stabilized by multiple interactions

Quaternary (subunit organization):

• Assembly of multiple polypeptide subunits

• Stabilized by same forces as tertiary

What bonds stabilize the protein structures?

Secondary

• H bonds

Tertiary and Quaternary

• H-bonds

• Ionic and hydrophobic interaction

• disulfide bonds

• van der waals

What dictates the folding of proteins?

by the order of AAs in the primary structure.

Six Principles Linking Structure and Function

1. FUNCTION DEPENDS ON STRUCTURE

• A protein's shape determines what it can do

2. STRUCTURE DEPENDS ON SEQUENCE + WEAK FORCES

• Primary sequence encodes the fold while non-covalent forces drive folding

3. THE NUMBER OF FOLDING PATTERNS IS LARGE BUT FINITE

• Only ~1,400 distinct folds exist, and new proteins typically adopt one of these established patterns.

4. GLOBULAR PROTEINS ARE MARGINALLY STABLE

• Net ΔG of folding: only -20 to -40 kJ/mol

• Compare: single covalent bond ≈ -350 kJ/mol

5. MARGINAL STABILITY FACILITATES MOTION

• Proteins exhibit conformational dynamics, continuously transitioning between closely related structural states.

6. MOTION ENABLES FUNCTION

• Conformational changes are essential for enzyme catalysis, signal transduction and molecular transport

What is the primary driving force for protein folding

hydrophobic effect

Hydrogen bonds form between

donor (N–H) and acceptor (C=O) groups

When are H-bonds the strongest?

When they are linear

What bonds/forces enable close packing in the protein core

van der Waals forces.

Burial of what is the primary driving force for protein folding

hydrophobic residues

Ionic interactions form between what? Where are they found?

Oppositely charged side chains (salt bridges / ion pairs)

• found on protein surfaces

What can disrupt ionic interaction?

High salt concentrations or changes in pH.

• changes in pH can disrupt ionic interactions, causing conformational changes or denaturation

What do van der waals forces arise from?

ransient dipoles (electron fluctuations)

Van der Waals forces are dependent on what?

Density

work together with hydrophobic effect

What are the 4 favorable thermodynamic contributions to protein folding (ΔG<0)?

1. Hydrogen bonds: Formation of stabilizing H-bonds.

2. Hydrophobic effect: Burial of hydrophobic residues.

3. Van der Waals: Numerous close-range contacts.

4. Electrostatic: Ionic interactions (salt bridges).

What are the 3 unfavorable thermodynamic contributions to protein folding (ΔG>0)?

1. Loss of conformational entropy (the protein chain becomes highly ordered).

2. Loss of side-chain rotational freedom (entropy lost).

3. Reduced backbone flexibility.

What is the net ΔGfolding​, and why is its magnitude a feature, not a flaw?

Net Result: ΔGfolding​≈−20 to −40 kJ/mol (a small, marginal stability).

• Why it's a feature: It keeps the protein stable but flexible. This allows for conformational changes, regulation, and controlled unfolding/degradation when needed.

How are peptides connected?

rigid peptide planes connected by hinges at each alpha carbon

The angle about the Cα-N bond is denoted ____

The angle about the Cα-C bond is denoted ____

as the phi (φ) angle

as the psi (ψ) angle

• both 180

Steric clashes

occur when atoms are too close together in a molecular structure, leading to unfavorable interactions that can destabilize the protein.

Why do proteins adopt specific, repeatable secondary structures?

Only ~20% of φ/ψ space is sterically allowed

Secondary structure folding patterns

regular, repeating conformations stabilized by BACKBONE hydrogen bonds

• Alpha helix - most common

• Beta sheets - extended strands, inner strand H-bonds

• Beta turn: reverse side chain direction, four residues

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