Motif formation from amino acid sequences

Secondary structure occurs mainly as a helices and p strands. The formation of secondary structure in a local region of the polypeptide chain is to some extent determined by the primary structure. Certain amino acid sequences favor either a helices or p strands others favor formation of loop regions. Secondary structure elements usually arrange themselves in simple motifs, as described earlier. Motifs are formed by packing side chains from adjacent a helices or p strands close to each other. 

Flg.1. In the amino acid sequence of KO-42 is encoded its fold and its function as it controls the formation of a hairpin helix-loop-helix motif that dimerizes to form a four-helix bundle. On the surface of the folded motif a reactive site is formed that catalyzes hydrolysis, transesterification and amidation reactions of reactive esters, whereas unfolded peptides are incapable of cooperative catalysis. In addition the values, and thus the reactivities, of the histidine residues are controlled by the fold. The pK of each His residue of KO-42 is shown in the figure and deviate by as much as 1.2 units from that of random coil peptides which is 6.4... 

The self-assembled amyloid fibrils exhibit distinct morphologies, often characterized as twisted or parallel assemblies of finer filaments in TEM images (Fig. 2c). The morphology of Ap (1-40) depends subtly on synthetic conditions, showing significantly different toxicities in neuronal cell cultures [32]. This shows that the structures of amyloid fibrils are not determined solely by the amino acid sequence. However, the sequence of the peptides is important as it controls the formation of the basic structural motifs. Because Ap (1-42) has a different sequence, the structure shows different features from Ap (1-40). Ap (1-42) also can be synthesized and form fibrils in vitro with slightly different conditions from that of Ap (1-40) and the structural information can be analyzed by the ssNMR as weU. Unlike Ap (1-40), it has been revealed that residues 1-17 are disordered and residues 18-26 and 31—42 form two intermolecular p-sheets in Ap (1-42) [33]. 

The functionalization of folded motifs is based on an understanding of secondary and tertiary structures (Fig. 2) and must take into account the relative positions of the residues, their rotamer populations and possible interactions with residues that do not form part of the site. For example, glutamic acid in position i has a strong propensity for salt-bridge formation, and thus reduced reactivity, if there is a Lys residue available i-4 in the sequence, but the probabihty is much less if the base is i-3 [60]. Fortunately, there is a wealth of structural information on the structural properties of the common amino acids from studies of natural proteins that provides considerable support for the design of new proteins. The naturally occurring amino acids have so far been used to construct reactive sites for catalysis [11-13], metal- and heme-binding sites [14,15,19,21,22] and for the site-selective functionalization of folded proteins [24,25]. 

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