protein folding and hydrophobic effect

where does protein folding typically occur and why?

usually occurs in aqueous environment

this is because the hydrophobic effect guides the process as hydrophobic side chains told together

what are the characteristics of hydrophobic/non-polar molecules?

• avoid water contact (water molecules form ‘cages’ around molecules)

• aggregate to release water molecules

where are hydrophobic/non-polar side chains located in a protein?

in the core/interior

where are hydrophilic side chains located in a protein?

on the surface (interact with aqueous environment)

where are hydrophobic and hydrophilic residues located in soluble proteins?

hydrophilic residues are on the surface (solubility)

hydrophobic residues in the core to provide structural stability

where are hydrophobic and hydrophilic residues located in transmembrane proteins?

hydrophobic residues on the surface to interact with hydrophobic interior of membrane, keeping protein in place

what is protein folding governed by?

thermodynamics

what does thermodynamics consist of?

balance between entropy (S) and enthalpy (H) which determines the free Gibb’s energy (G) of the system

what is entropy?

measure of disorder of a system

• e.g. entropy decreases when a protein folds as the polypeptide chain loses freedom of movement

what is enthalpy?

internal energy of a system (electrostatic interactions, hydrogen bonds…)

what is the equation for free energy

ΔG = ΔH - TΔS

what happens to entropy during protein folding?

• entropy increases due to the hydrophobic effect

• even though the polypeptide chain is becoming more ordered, the hydrophobic effect has a larger impact (hydrophobic amino acids clustering in core)

what happens to enthalpy during protein folding?

• enthalpy decreases due to formation of favourable interactions (exothermic) increasing stability

  • energy is released when bonds/interactions are formed

Gibbs free energy of a folded vs unfolded protein

folded protein has less free Gibbs energy

• more thermodynamically stable

• low energy, low entropy

how can small proteins fold?

can fold spontaneously through the hydrophobic effect

how do large/multi-domain proteins fold?

use chaperones to help with folding

what are chaperones?

group of proteins that interact with unfolded or improperly folded proteins

prevent non-specific aggregation by binding to hydrophobic regions or providing microenvironment

different families of chaperones exist

what happens to misfolded proteins?

proteasomes break them down and recycle constituent parts that can be used again