Rucete ✏ Lehninger Principles of Biochemistry In a Nutshell
4.1 Overview of Protein Structure
This chapter introduces the major physical and chemical principles that determine protein structure, explains the role of weak interactions and the peptide bond, and outlines the conformational constraints of polypeptide chains.
Protein Conformation and Stability
• Proteins can theoretically adopt many conformations, but only one or a few (the native conformations) predominate under biological conditions due to thermodynamic stability (lowest free energy).
• Some proteins or regions are intrinsically disordered yet still functional.
• Native protein structures are only marginally stable, with a small free energy difference between folded and unfolded states.
• Weak, noncovalent interactions—including hydrogen bonds, hydrophobic interactions, ionic interactions, and van der Waals forces—are the main stabilizing forces in protein structure.
• Covalent disulfide bonds are strong but relatively rare, more common in extracellular and thermophilic proteins.
The Hydrophobic Effect and Protein Folding
• The hydrophobic effect is the major driving force for protein folding: hydrophobic amino acid side chains cluster in the interior, increasing the entropy of water and stabilizing the folded form.
• Formation of intramolecular hydrogen bonds and burial of hydrophobic groups together lead to a stable protein core.
• Polar or charged groups inside the protein must find partners for hydrogen bonding or ionic interactions; unpaired polar groups in the core are destabilizing.
• Ion pairs (salt bridges) can also stabilize protein structure, especially when buried within the protein.
• Van der Waals interactions, though individually weak, collectively contribute significant stabilization when atoms are closely packed.
Covalent Structure and Dihedral Angles
• The peptide bond is rigid and planar due to partial double-bond character from resonance, limiting rotation.
• Polypeptide backbone conformation is described by three dihedral (torsion) angles: ϕ (phi), ψ (psi), and ω (omega).
• Rotation is possible about the ϕ and ψ bonds but is limited by steric hindrance; the peptide bond (ω) is usually fixed in the trans configuration.
• These conformational constraints restrict the possible folded structures of proteins.
In a Nutshell
• Protein structure is determined by weak, noncovalent forces—mainly the hydrophobic effect, hydrogen bonds, ionic interactions, and van der Waals forces—rather than covalent bonds.
• The peptide bond’s rigidity and the limited rotation around backbone bonds define the range of possible conformations and thus the higher-order structure of proteins.
• Understanding these principles is essential for analyzing protein folding, stability, and function.