Capturing protein folding-relevant topology via absolute contact order variants

Abstract

Absolute contact order is one of the simplest parameters used to predict protein folding rates. Many variants of contact order (CO) have been applied to highlight different aspects of contact neighborhoods and their relationship to folding. However, a systematic study of the influence of CO variants on correlation with folding rate has not been performed for a large combined set of multi- and two-state proteins. We explore different contact neighborhoods and resulting CO by varying the distance thresholds and weighting of sequence separation for heavy atom and residue-based counting methods for a set of 136 proteins diverse across folding and structural classes. We examine the changes in contact neighborhoods and compare correlations with our CO variants and the protein folding rates across our data set as well as by folding type and structural class. Different CO variants lead to the strongest correlations within each protein structural class. Our results demonstrate that backbone topology at a distance beyond where energetic interactions dominate is able to capture folding determinants, and suggest that more sensitive methods of characterizing contact relationships may improve ln kf prediction for diverse protein sets.