Elucidating the mechanism of protein folding is an intriguing and challenging task. In the past decade tremendous advances have been made in our knowledge of protein folding (1). From the knowledge of long-range contacts (contacts between two residues that are close in space and far in the sequence) in protein structure we have proposed a novel parameter, long-range order (LRO) for a protein (2). LRO is defined as, LRO = Snij/N; nij = 1 if |i-j| > 12; nij = 0 otherwise, where i and j are two residues in which the Ca distance between them is £ 8Å and N is the total number of residues in a protein. We observed a strong inverse relationship (r = -0.78) between LRO and experimental folding rate, ln(k) for a set of 23 proteins that fold via a two-state mechanism. Further, we developed a simple statistical model for predicting the protein folding rates from the knowledge of LRO and we found an excellent agreement between the predicted folding rates and experimental observations.
We have related the experimental F-values upon mutations with the changes in various amino acid properties [DP(i) = Pmut (i) - Pwild (i), where, Pmut (i) and Pwild (i), are, respectively, the property value of the ith mutant and wild type residue] using correlation coefficient. Further, we have included the effect of local sequence and structural information. We found that the relationship between conformational properties and F values determines the presence/absence of secondary structures in the transition state. In buried mutations, the physical and thermodynamic properties have significant correlation with F. The short and medium-range energy (Esm) strongly correlated with F values for the partially buried mutants, expressing the importance of medium-range interactions in transition state structures. In exposed mutations, the properties reflecting long-range interactions show significant correlation with F values. In essence, medium and long-range interactions are very important to understand the mechanism of protein folding.
References: 1. M.M. Gromiha and S. Selvaraj (Eds). Recent Research Developments in Protein Folding, Stability and Design. Research Signpost, Trivandrum, India (2002). 2. M.M. Gromiha and S. Selvaraj (2001) J. Mol. Biol. 310, 27-32. 3. M.M. Gromiha and S. Selvaraj (2002) FEBS Letters 526, 129-134.