Sampling Kinetic Protein Folding Pathways using All-Atom Models Bolhuis

Bolhuis Sampling Kinetic Protein Folding Pathways using All-Atom Models, Lect. Notes Phys. 703, 393-433 (2006) 

Before proteins can actively function in the living cell they must fold up into a specific 3-dimensional structure, the so-called native state (see Fig. 1). Already in the 1960 s it was recognized that the long linear polypeptides chains can adopt their native structure starting from the random coil state in a surprisingly short time. The famous Levinthal paradox states that if a peptide bond between amino acids can only adopt two conformations a relatively short protein of a hundred residues can have around 2 10 possible 

The fact that proteins spontaneously fold to their native state requires a physical explanation. An unfolded or denatured protein makes many interactions with the solvent (water), and as the protein folding proceeds, these interactions are exchanged with intra-molecular non-covalent bonds, such as hydrogen bonds or salt-bridges [2]. Many hydrogen bond donors and acceptors make intra-molecular pairs to form secondary structures such as alpha helices and beta sheets (see Fig. 1). Each of these bonds adds a small energetic contribution to the stability of the native state, but added together the 

Two state kinetics does not necessarily obey the van t Hoff-Arrhenius law, which presumes a linear relation between the logarithm of the rate constant and the inverse temperature. As for proteins both energetic and entropic contributions are important a more general applicable expression for the rate constant is given by transition state theory (TST) 

As the balance between entropy and energy is by construction taken into account in the funnel landscape, temperature denaturation is conceptually explained. However, the down hill process does not clearly exhibit the free 

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