Deciphering the folding mechanism of proteins is significant to comprehend
their physiological functions. In this chapter, several significant and yet common factors
of protein folding have been discussed: 1) Space limitation (confinement and
macromolecular crowding). Proteins are confined and crowded in cellular
circumstances, which facilitates the folding and enhances the stability through the
entropic reduction of the unfolded states. 2) Solvent effects. The various solvation
models have been described. Water is more than the environment, and can also
participate in the folding by mediating the collapse of protein chains and searching for
the native topologies along the free energy landscapes. 3) Pressure, temperature and pH.
The high hydrostatic pressure induces the volume decrease, destroys the non-covalent
interactions and increases the roughness of free energy landscape, which generally
drives the equilibrium toward the unfolded states. pH modulates protein structure and
dynamics through protonation/deprotonation of sidechains and sometimes causes the
misfolding. Temperature changes alter the conformational dynamics but not the folding
pathway. 4) Structural modifications (mutation, truncation/insertion and
protonation/deprotonation). The mutations of key residues significantly alter the folding
by distorting the cooperative interactions, which can result in the misfolding or
aggregation; nonetheless, the rational design by mutations can be beneficial to protein
folding. The proper truncations do not show obvious influences on protein structure and
dynamics, and the loop insertions may reduce the unfolding free energy barrier and
facilitate the unfolding kinetics. Protonation of key residues affects significantly the
folding/unfolding equilibrium by altering the non-covalent interactions.
Keywords: Confinement, conformational dynamics, cooperative interactions,
denaturation and aggregation, folding/unfolding kinetics, free energy landscape, h-bonding, hydrophobic core, macromolecular crowding, misfolding, molecular
dynamics, mutation, non-covalent interactions, ph, pressure, protein folding,
solvation models, solvent effects, structural modification, temperature.
