Analysis of Rate-limiting Long-range Contacts in the Folding Rate of Three-state and Two-state Proteins

B.      Harihar; S.      Selvaraj

Abstract

In the past decade, when compared to models describing the folding rates of two-state proteins, models describing the folding mechanism of three-state proteins remain quite limited due to the complexity present in the folding mechanism and lack in their experimental data. In the present work, rate-limiting long-range contacts were classified into various bins based on sequence separation distance between the contacting residues and the role of these bins were analyzed for their importance in a data set of 35 three-state proteins. Predicting the folding rates of these proteins have been carried out by relating experimental folding rates and long-range contacts obtained from various sequence separation bins. For comparison, using the present model, prediction of the folding rates of 45 two-state proteins also resulted with good accuracy. Our method shows that long-range contacts observed in the final 3-D structure of proteins at various sequence separation bins are found to be an important descriptor in explaining the folding rates of three-state proteins and suggest that formation of contacts between residues present at these sequence separation distance may be a crucial factor in deciding structure formation and folding rates of these proteins. The aim of our present work is not to construct a new descriptor for the folding rates of three-state proteins, nor is to provide improved means of folding-rate prediction for these proteins. We tend to elucidate that how long-range contacts play a crucial role in the folding mechanism of three state proteins belonging to three major structural classes and implication of these observations due to rate-limiting long-range contacts has been discussed in the light of other experimental studies of protein folding.

Keywords: Correlation coefficient, contact formation, folding rate prediction, long-range contacts, sequence separation distance, three-state proteins, Contact Order, LRO, TCD, FORTRAN program, jack-knife methods, NMR study, AABUF, Trp-cage, hydrogen bonding patternCorrelation coefficient, contact formation, folding rate prediction, long-range contacts, sequence separation distance, three-state proteins, Contact Order, LRO, TCD, FORTRAN program, jack-knife methods, NMR study, AABUF, Trp-cage, hydrogen bonding pattern