The Protein Non-Folding Problem: Amino Acid Determinants of Intrinsic Order and Disorder

Abstract

To investigate the determinants of protein order and disorder, three primary and one derivative database of intrinsically disordered proteins were compiled. The segments in each primary database were characterized by one of the following: X-ray crystallography, nuclear magnetic resonance (NMR), or circular dichroism (CD). The derivative database was based on homology. The three primary disordered databases have a combined total of 157 proteins or segments of length à "à vuà ' à rvqrà uvyrà urà qrvhvrà qhhihrà phvà $&! proteins from 32 families with 52,688 putatively disordered residues. For the four disordered databases, the amino acid compositions were compared with those from a database of ordered structure. Relative to the ordered protein, the intrinsically disordered segments in all four databases were significantly depleted in W, C, F, I, Y, V, L and N, significantly enriched in A, R, G, Q, S, P, E and K, and inconsistently different in H, M, T, and D, suggesting that the first set be called order-promoting and the second set disorder-promoting. Also, 265 amino acid properties were ranked by their ability to discriminate order and disorder and then pruned to remove the most highly correlated pairs. The 10 highest-ranking properties after pruning consisted of 2 residue contact scales, 4 hydrophobicity scales, 3 scales associated vuà urrà hqà rà yhvà phyrà à Vvtà urrà à rvrà sà phvà sà urà " primary databases suggests that disorder in all 3 databases is very similar, but with those characterized by NMR and CD being the most similar, those by CD and X-ray being next, and those by NMR and X-ray being the least similar.

Hubsm: A Novel Amino Acid Substitution Matrix for Comparing Hub Proteins

“…4 the mutability of each amino acid residue were studied. As reported earlier, the computed amino acid substitution matrix coincides with the favorable amino acids proposed by Williams et al [18]. Substitution of amino acids by disfavorable residue to a preferred residue yields a large negative score in the substitution matrix.…”

“…Also these amino acids evolve at a different mutation rate [17]. Amino acids of disorder region lacks hydrophobic amino acid, contains more hydrophilic and charged residues [18] and, the low complexity region is enriched with cysteine and glutamine amino acids [19].…”

“…Disorder regions of hub proteins contains very few hydrophobic amino acids. According to Williams et al [18] disordered regions of hub proteins have a propensity for amino acids alanine, arginine, glycine, glutamine, serine, proline, glutamic acid and lysine (A, R,G, Q, S, P, E and K). Similarly it disfavors the presence of amino acids such as Tryptophan, cysteine, phenylalanine, isoleucine, tyrosine, valine and Asparagine (W, C, F, I, Y, V, L and N).…”

“…Also these amino acids evolve at a different mutation rate [17]. Amino acids of disorder region lacks hydrophobic amino acid, contains more hydrophilic and charged residues [18] and, the low complexity region is enriched with cysteine and glutamine amino acids [19].The importance of hub proteins in interaction networks and signalling pathways have aided in developing many computational tools and structural studies. These approaches require similarity search and sequence alignment as the preliminary step.…”

Prediction of disorder with new computational tool: BVDEA

“…Recently, it was confirmed that some disordered proteins can also be involved in several diseases such as Alzheimer disease, Parkinson disease and certain types of cancer (Williams et al, 2001;Galzitskaya et al, 2006) Therefore, studies on structural identification of intrinsically disordered proteins have been thought to be an aid in drug design, protein expression and functional recognition. Due to their significance, dealing with structural identification of the proteins that was named as "The Protein Non-Folding Problem" has gained growing interest in structural bioinformatics (Li et al, 2000).…”