On the role of structural class of a protein with two‐state folding kinetics in determining correlations between its size, topology, and folding rate

Abstract

The time it takes for proteins to fold into their native states varies over several orders of magnitude depending on their native-state topology, size, and amino acid composition. In a number of previous studies, it was found that there is strong correlation between logarithmic folding rates and contact order for proteins that fold with two-state kinetics, while such correlation is absent for three-state proteins. Conversely, strong correlations between folding rates and chain length occur within three-state proteins, but not in two-state proteins. Here, we demonstrate that chain lengths and folding rates of two-state proteins are not correlated with each other only when all-a, all-b, and mixed-class proteins are considered together, which is typically the case. However, when considering all-a and all-b two-state proteins separately, there is significant linear correlation between folding rate and size. Moreover, the sets of data points for the all-a and all-b classes define asymptotes of lower and upper limits on folding rates of mixed-class proteins. By analyzing correlation of other topological parameters with folding rates of two-state proteins, we find that only the long-range order exhibits correlation with folding rates that is uniform over all three classes. It is also the only descriptor to provide statistically significant correlations for each of the three structural classes. We give an interpretation of this observation in terms of Makarov and Plaxco's diffusion-based topomer-search model.

Microsecond acquisition of heterogeneous structure in the folding of a TIM barrel protein

“…Continuous-flow microchannel mixing methods interfaced to small-angle x-ray scattering (SAXS), circular dichroism (CD), time-resolved Förster resonant energy transfer (trFRET), and time-resolved fluorescence anisotropy (trFLAN) have been used to directly monitor global and specific dimensional properties of the partially folded state in the microsecond time range for a representative (␤␣) 8 FRET ͉ microsecond mixing ͉ misfolding ͉ small-angle x-ray scattering T he funnel shape of typical protein folding-energy landscapes suggests that sequences have evolved to minimize energetic and topological frustration (1,2). This view is supported by the twostate folding of many small proteins (3) and the significant correlation of their folding rates with native topology (4,5). Morecomplex mechanisms, typical of larger proteins, often place intermediates on a progressive path to the native conformation.…”

Intrinsic Relationship of Amino Acid Composition/Occurrence with Topological Parameters and Protein Folding Rates

“…Long-range order is reported to be a parameter that explains well the folding rates in all structural classes of proteins [4]. The amino acid occurrence improved the correlation in all-class proteins whereas there is no appreciable change in the correlation of other two structural classes as well as the classification based on folding types.…”

“…where, i and j are contacting residues, nr and nc are, respectively, number of residues and number of contacts in a protein [4]. The summation is done for any cutoff residue separation (l cut ) and if |i-j| > l cut .…”

“…Gromiha and Selvaraj [3] defined a novel parameter, long-range order (LRO) from the knowledge of long-range contacts (contact between two residues that are close in space and far in the sequence) in protein structure and established a simple statistical model for predicting the protein folding rates. Recently it has been reported that LRO is the only parameter that shows excellent correlation with the folding rates of all structural classes of proteins [4]. These two parameters, CO and LRO are incorporated into a new parameter, total contact distance (TCD), which shows a good relationship with protein folding rates [5].…”

Global and local prediction of protein folding rates based on sequence autocorrelation information

“…They developed a simple statistical model to predict the folding rates. Recently, there was evidence that LRO was the only parameter that showed high correlation with the folding rates of all structural classes of proteins (Istomin et al, 2007). Subsequently, total contact distance (TCD) (Zhou and Zhou, 2002), which was the summation over all the contacts of each residue, showed a correlation coefficient of À 0.88 with protein folding rates.…”