Jitao Huang

Amino acid sequence predicts folding rate for middle-size two-state proteins

The significant correlation between protein folding rates and the sequence‐predicted secondary structure suggests that folding rates are largely determined by the amino acid sequence. Here, we present a method for predicting the folding rates of proteins from sequences using the intrinsic properties of amino acids, which does not require any information on secondary structure prediction and structural topology. The contribution of residue to the folding rate is expressed by the residues Ω value. For a given residue, its Ω depends on the amino acid properties (amino acid rigidity and dislike of amino acid for secondary structures). Our investigation achieves 82% correlation with folding rates determined experimentally for simple, two‐state proteins studied until the present, suggesting that the amino acid sequence of a protein is an important determinant of the protein‐folding rate and mechanism. Proteins 2006.

Secondary structure length as a determinant of folding rate of proteins with two‐ and three‐state kinetics

We present a simple method for determining the folding rates of two‐ and three‐state proteins from the number of residues in their secondary structures (secondary structure length). The method is based on the hypothesis that two‐ and three‐state foldings share a common pattern. Three‐state proteins first condense into metastable intermediates, subsequent forming of α‐helices, turns, and β‐sheets at slow rate‐limiting step. The folding rate of such proteins anticorrelate with the length of these β‐secondary structures. It is also assumed that in two‐state folding, rapidly folded α‐helices and turns may facilitate formation of fleeting unobservable “intermediates” and thus show two‐state behavior. There is an inverse relationship between the folding rate and the length of β‐sheets and loops. Our study achieves 94.0 and 88.1% correlations with folding rates determined experimentally for 21 three‐ and 38 two‐state proteins, respectively, suggesting that protein‐folding rates are determined by the secondary structure length. The kinetic kinds are selected on the basis of a competitive formation of hydrophobic collapse and α‐structure in early intermediates. Proteins 2007.

Differentiation between two-state and multi-state folding proteins based on sequence.

Prediction of protein‐folding rates follows different rules in two‐state and multi‐state kinetics. The prerequisite for the prediction is to recognize the folding kinetic pathway of proteins. Here, we use the logistic regression and support vector machine to discriminate between two‐state and multi‐state folding proteins. We find that chain length is sufficient to accurately recognize multi‐state proteins. There is a transition boundary between two kinetic models. Protein folds with multi‐state kinetics, if its length is larger than 112 residues. The logistic prediction from amino acid composition shows that the kinetic pathway of folding is closely related to amino acid volume. Small amino acids make two‐state folding easier, and vice versa. However, cysteine, alanine, arginine, lysine, histidine, and methionine do not conform to this rule. Proteins 2008.

Prediction of folding transition-state position (βT) of small, two-state proteins from local secondary structure content

Folding kinetics of proteins is governed by the free energy and position of transition states. But attempts to predict the position of folding transition state on reaction pathway from protein structure have been met with only limited success, unlike the folding‐rate prediction. Here, we find that the folding transition‐state position is related to the secondary structure content of native two‐state proteins. We present a simple method for predicting the transition‐state position from their α‐helix, turn and polyproline secondary structures. The method achieves 81% correlation with experiment over 24 small, two‐state proteins, suggesting that the local secondary structure content, especially for content of α‐helix, is a determinant of the solvent accessibility of the transition state ensemble and size of folding nucleus. Proteins 2007.