RESUMO
Nonoverlapping closed loops of around 25-35 amino acids formed via nonlocal interactions at the loop ends have been proposed as an important unit of protein structure. This hypothesis is significant as such short loops can fold quickly and so would not be bound by the Leventhal paradox, giving insight into the possible nature of the funnel in protein folding. Previously, these closed loops have been identified either by sequence analysis (conservation and autocorrelation) or studies of the geometry of individual proteins. Given the potential significance of the closed loop hypothesis, we have explored a new strategy for determining closed loops from the insertions identified by the structural alignment of proteins sharing the same overall fold. We determined the locations of the closed loops in 37 pairs of proteins and obtained excellent agreement with previously published closed loops. The relevance of NMR structures to closed loop determination is briefly discussed. For cytochrome c, cytochrome b(562) and triosephophate isomerase, independent folding units have been determined on the basis of hydrogen exchange experiments and misincorporation proton-alkyl exchange experiments. The correspondence between these experimentally derived foldons and the theoretically derived closed loops indicates that the closed loop hypothesis may provide a useful framework for analyzing such experimental data.
Assuntos
Dobramento de Proteína , Proteínas/química , Alinhamento de Sequência , Alcanos/química , Aminoácidos/química , Grupo dos Citocromos b/química , Citocromos c/química , Proteínas de Escherichia coli/química , Hidrogênio/química , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Análise de Sequência de Proteína , Triose-Fosfato Isomerase/químicaRESUMO
The closed loop hypothesis of Berezovsky and Trifonov implicates the closure of loops of length 25-35 through hydrophobic interactions at the 'locks' as a key event in protein folding. The hypothesis is supported by published analyses of nine major superfolds. Here, we have generated multiple sequence alignments for the nine superfolds with PDB codes lthb, 1ilb, 256b, 2rhe, 1aps, 2stv, 4fxn (2fox), lubq and 7tim and have analysed the degree of conservation at the loop ends. Seventy percent of these loop ends are found to be well conserved and the peak in the distribution of distances between these well conserved regions lies at around 25 residues; both observations are consistent with the Berezovsky and Trifonov's hypothesis.