How the folding rates of two- and multistate proteins depend on the amino acid properties

Abstract

Proteins fold by either two-state or multistate kinetic mechanism. We observe that amino acids play different roles in different mechanism. Many residues that are easy to form regular secondary structures (α helices, β sheets and turns) can promote the two-state folding reactions of small proteins. Most of hydrophilic residues can speed up the multistate folding reactions of large proteins. Folding rates of large proteins are equally responsive to the flexibility of partial amino acids. Other properties of amino acids (including volume, polarity, accessible surface, exposure degree, isoelectric point, and phase transfer energy) have contributed little to folding kinetics of the proteins. Cysteine is a special residue, it triggers two-state folding reaction and but inhibits multistate folding reaction. These findings not only provide a new insight into protein structure prediction, but also could be used to direct the point mutations that can change folding rate.

Reduced alphabet for protein folding prediction

“…As far as the reduced alphabet is concerned, roughly speaking, the folding‐promoting ability increases progressively with increase in hydrophobic character of the amino acids (Fig. ), which is consistent with our previous observations …”

“…Subsequently, efforts have further been made to predict protein folding rates from their secondary structure assignment or amino acid sequence to mine the necessary information to make up the correct 3D structure. In our previous study, we also observed that folding rates, transition state position and folding kinetic type of proteins are well correlated to their secondary structure content or amino acid composition …”

“…5), which is consistent with our previous observations. 43,44 Cysteine is a hydrophobic amino acid having a thiol group; two thiol groups are susceptible to oxidation to form the disulfide bridge that is a rate-limiting step in many folding reactions. Thus, the cysteine residues may significantly slow folding rate.…”

“…In our previous study, we also observed that folding rates, transition state position and folding kinetic type of proteins are well correlated to their secondary structure content 39,40 or amino acid composition. [41][42][43][44] These prompt the question of whether there is a minimal alphabet with could be used to predict protein folding rates. The folding rates of the simplified proteins are compared to that of the corresponding wild type proteins.…”