The RNA model

Three-dimensional structures of RNA molecules are hard to predict, since experimental information on relations ofbiopolymer sequences and structures is rare. Three-dimensional structures at atomic resolution are unique in the sense that there are no two sequences 

DISTRIBUTION OF COMMON STRUCTURES IN THE GCJ0 REFERENCE CASE OBTAINED BY FOLDING ALL GC-ONLY SEQUENCES OF CHAIN LENGTH n = 30 

Rank r Size of the neutral network m Sequence of components Z 

DISTRIBUTION OF RARE STRUCTURES IN THE GC30 REFERENCE CASE 

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Bnilding on the fonndation of these stndies, Haddad et al. used rings I and II of paromomycin (called paromomine) as the minimum structural motif in a computational search of over 273,000 componnds that might bind an A-site template. Results of this search were then narrowed based on steric and energetic demands. Several componnds were snbseqnently synthesized and shown to bind to an RNA model of the A-site, with some of the compounds (e.g., 2) exhibiting broad-spectrum activity in bacteria. X-ray strnctnres with the RNA models and with the 30S ribosome vindicated the design principles. The compounds do bind to the A-site and they do flip the two bases mentioned previously to the extrahelical position, as do other antibiotics of this class. 

Many artificial systems have been designed recently to imitate the function and behaviour of native enzymes - biomimetic chemistry [27]. Among them, calixarene-based receptors bearing one, two or three Zn(II) complexes on the upper rim were prepared as a model for phosphoesterases [28-31]. Dinuclear receptor 25 was reported to enhance the rate of transesterification of the RNA model substrate 2-hydroxypropyl-p-nitrophenyl phosphate more than 20,000 times compared with the non-catalysed reaction. The complexation mode for the phosphate anion can be described as cascade complexation where the anion is coordinated within the cavity formed by two zinc cations. 

For transition metals and Zn(II), how might metal complexes be designed to promote rapid cleavage of RNA One approach is the functionalization of ligands to participate in catalysis. The N-methyl-CR ligand was modified to contain a basic group for bifunctional catalysis (21). A Zn(II) complex of one of the modified macrocycles was shown to accelerate cyclization of the RNA model substrate 1 (1 = 4-nitrophenylphosphate ester of propylene glycol) 20-fold more rapidly than the Zn(II) complex of N-methyl-CR. 

In recent years, methods for the catalytic cleavage of the P-O bond in phosphate esters have been developed. It is now reported that a cyclic P-sheet peptide -based binuclear zinc (II) complex markedly accelerated the cleavage of the phosphodiester linkage of the RNA model substrate 2-hydroxypropyl p-nitro-phenyl phosphate (102) (Scheme 17). °... 

A zinc complex of the BPAN (2,7-bis[2-(2-pyridylethyl)aminomethyl]-l,8-naphthyridine ligand, [(BPAN)Zn2(p-0H)(p-Ph2P02)](C104)2, Fig. 27) catalyzes the transesterification of the RNA model substrate HPNP (2-hydroxypropyl 4-nitro-phenyl phosphate (Fig. 40, bottom) in aqueous buffered solution (HEPES) containing 1% CH3CN.141 The rate of this reaction was found to be 7 times fast than the reaction catalyzed by a mononuclear Zn(II) complex of bpta (Fig. 25). A pH-rate... 

Artificial phosphodiesterases that combine a guanidinium unit with a general base connected by a m-xylylene linker catalyse the transesterification of the RNA model compound 2-hydroxypropyl /t-nitrophenyl phosphate (Scheme 20 e.g., B = imidazole). The bifunctional catalysts showed varying extents of cooperation between catalytic units, and a rate enhancement of 4 x 10" was seen in the most favourable case. ... 

It is of interest to note that the model proposed by these authors for poly-L-lysine-DNA complex is quite different from the RNA to poly-L-lysine model described above. They concluded that a molecular model similar to that of deoxyribonucleoprotamine proposed by Wilkins (1956) would be acceptable for the poly-L-lysine DNA complex. In this model, an almost fully extended polypeptide chain also winds helically around the double-stranded polynucleotide chains. Unlike the RNA model, however, the pitch of the polypeptide helix is the same as that of the polynucleotide helices This model requires one amino acid residue per one nucleotide residue, i.e., NH tP = 1 1, as is experimentally observed. On the other hand, this... 

This approach was recently extended to target the cleavage of RNA model compounds." A polypeptide that adopts a characteristic helix-loop-helrx conformation and accelerates the hydrolysis of the RNA model substrate 2-hydroxypropyl 4-nitrophenyl phosphate (HPNP) by about 2 orders of magnitude was used in this investigation. Two histidine and two arginine units in this peptide were believed to be responsible for catalytic activity. Analogs of... 

The bimetallic complex 2—Zu2 is a highly efficient turnover catalyst of the transesterification of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) (Eq. 26.1). A 23,000-fold rate enhancement is observed in the presence of 2—Zn2 (0.48 mM catalyst concentration, 50 % MeCN-20 mM aqueous buffer, pH 7,25 °C) [16]. The two metal ions in 2—Zn2 efficiently cooperate both in... 

Another outstanding study on the usage of an effective calixarene derivative as a biomimetic catalyst for the cleavage of the RNA model compound, 2-hydroxypropyl p-nitrophenyl phosphate was reported by Baldini et al. [35]. They prepared four calix[4]arene derivatives substituted with two to four guadinium moieties at the upper rim of calixarenes, and investigated their catalytic affinities in the cleavage of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate in water (see Figs. 27.17 and 27.18). They found that the... 

Fig. 27.18 Cleavage of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate in the presence of calixarene-based pseudo-biocatalyst [35]...

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