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[Use of the computer simulation method of complementary amino acids base on a genetic code algorithm for the search for new peptide compounds belonging to tuftsin-like activity].

Methods of k-neighbours and neural networks were used for prediction of pharmacological effects of new compounds wits tuftsin-like activities. The tested compounds were constructed by the complementarity rule of genetic code algorithm. Five of seven substitutions with stereocomplement amino acids in the tuftsin sequence lead to new active compounds. Thus, the use of amino acid complementary code can be a helpful tool for the construction of a new immunomodulating peptide.

Algorithms↗

[The tricarboxylic acid cycle and the genetic code].

Application of quantum--mechanical calculations of interaction energy of nitrous bases in DNA triplets to genetic code permits division of codons and pertinent amino acids into two groups. The first one corresponds to the upper energetic level 150-170 kJ/mole per base pair (per a triplet codon on the average). The second group corresponds to the low energetic level 88/92 kJ/mole per base pair. Comparing this grouping of amino acids with their incorporations into the cycle of tricarboxylic acids it turns out that the majority of amino acids of the first group are incorporated into the cycle via acetyl-KoA. Most amino acids of the second group are incorporated directly. It seems that the ways of amino acids introduction into the cycle of tricarboxylic acids are to a certain degree predetermined by energetic interactions of nitrous bases in the genetic codons.

Amino Acids↗

Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process.

The aminoacyl-tRNA synthetases (AARSs) and their relationship to the genetic code are examined from the evolutionary perspective. Despite a loose correlation between codon assignments and AARS evolutionary relationships, the code is far too highly structured to have been ordered merely through the evolutionary wanderings of these enzymes. Nevertheless, the AARSs are very informative about the evolutionary process. Examination of the phylogenetic trees for each of the AARSs reveals the following. (i) Their evolutionary relationships mostly conform to established organismal phylogeny: a strong distinction exists between bacterial- and archaeal-type AARSs. (ii) Although the evolutionary profiles of the individual AARSs might be expected to be similar in general respects, they are not. It is argued that these differences in profiles reflect the stages in the evolutionary process when the taxonomic distributions of the individual AARSs became fixed, not the nature of the individual enzymes. (iii) Horizontal transfer of AARS genes between Bacteria and Archaea is asymmetric: transfer of archaeal AARSs to the Bacteria is more prevalent than the reverse, which is seen only for the "gemini group. " (iv) The most far-ranging transfers of AARS genes have tended to occur in the distant evolutionary past, before or during formation of the primary organismal domains. These findings are also used to refine the theory that at the evolutionary stage represented by the root of the universal phylogenetic tree, cells were far more primitive than their modern counterparts and thus exchanged genetic material in far less restricted ways, in effect evolving in a communal sense.

Amino Acids↗

The genetic code and error transmission.

The amino acid substitutions resulting from single-base substitution in the natural genetic code have been compared with those resulting from single-base substitutions in computer-generated random codes. Considering the amino acid properties of molecular weight, polar requirement, number of dissociating groups, pK(1)', isoelectric point, and alpha-helix forming ability, it is concluded that, for the natural code, single-base substitution in the first position of the codon tends to result in the substitution of an amino acid more similar to the original amino acid than would be expected from a random code. In the natural code, the second position of the codon plays the largest role in determining the properties of the amino acid.

Amino Acid Sequence↗

A real-coded genetic algorithm for training recurrent neural networks.

The use of Recurrent Neural Networks is not as extensive as Feedforward Neural Networks. Training algorithms for Recurrent Neural Networks, based on the error gradient, are very unstable in their search for a minimum and require much computational time when the number of neurons is high. The problems surrounding the application of these methods have driven us to develop new training tools. In this paper, we present a Real-Coded Genetic Algorithm that uses the appropriate operators for this encoding type to train Recurrent Neural Networks. We describe the algorithm and we also experimentally compare our Genetic Algorithm with the Real-Time Recurrent Learning algorithm to perform the fuzzy grammatical inference.

Algorithms↗

Hemoglobin and the genetic code. Evolution of protection against somatic mutation.

One-half of the twenty amino acids of the genetic code are just one mutational step away from the chain-terminator codons UAA, UAG, and UGA. It is postulated that somatic mutation to terminator is a hazard to which the organism has and to respond by adjusting certain proteins in the direction of fewer mutable residues. This view is supported by calculations based on the primary structure of five of the human hemoglobin chains. Each chain is scored for mutability to terminator in accord with the numbers and kinds of amino acids present. Among the adult chains, the most essential one, the alpha, has lowest mutability. The beta and delta follow, and in order of the presumed harm to the organism of a shortage of chain copies. Ante-natal chains tend to have higher mutabilities, supporting the view that cumulative mutational change in DNA can do little if the gene ceases to transcribe early in life. Two other predicitons based on the supposition of effective selection against mutability to terminator are also met: chain length of polypeptides is negatively correlated with their scores for mutability to terminator, and examination of the recently determined sequence of beta messenger RNA shows preferential use of codons that are not readily mutable to terminator.

Amino Acid Sequence↗

The fidelity of the translation of the genetic code.

Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in structure but also in chemical nature. A 'double-sieve' editing model was proposed in the late seventies to explain how two closely related amino acids may be discriminated. However, a clear understanding of this mechanism required structural information on synthetases that are faced with such a problem of amino acid discrimination. The first structural basis for the editing model came recently from the crystal structure of isoleucyl-tRNA synthetase, a class I synthetase, which has to discriminate against valine. The structure showed the presence of two catalytic sites in the same enzyme, one for activation, a coarse sieve which binds both isoleucine and valine, and another for editing, a fine sieve which binds only valine and rejects isoleucine. Another structure of the enzyme in complex with tRNA showed that the tRNA is responsible for the translocation of the misactivated amino-acid substrate from the catalytic site to the editing site. These studies were mainly focused on class I synthetases and the situation was not clear about how class II enzymes discriminate against similar amino acids. The recent structural and enzymatic studies on threonyl-tRNA synthetase, a class II enzyme, reveal how this challenging task is achieved by using a unique zinc ion in the active site as well as by employing a separate domain for specific editing activity. These studies led us to propose a model which emphasizes the mirror symmetrical approach of the two classes of enzymes and highlights that tRNA is the key player in the evolution of these class of enzymes.

Amino Acids↗

An unusual genetic code in nuclear genes of Tetrahymena.

We have cloned and partially sequenced two histone H3 genes of Tetrahymena thermophila. The DNA sequences strongly suggest that both genes are active in the vegetatively growing cell. Comparison of the derived amino acid sequences of these two genes with the actual sequence of Tetrahymena histone H3 results in the surprising conclusion that TAA codes for glutamine. This represents the first demonstration of a coding function for this termination codon of the "universal" code. This observation has important implications for the evolution of ciliates and of the genetic code.

Amino Acid Sequence↗

Periodical changes of amino acid reactivity within the genetic code.

Enthalpies (delta H++) and entropies (delta S++) of activation for the reaction of 18 N'-hydroxysuccinimide esters of N-protected proteinaceous amino acids with p-anisidine were measured and free enthalpies of activation (delta G++) at 25 degrees C were calculated on this basis. A regular correlation between delta G++s and the corresponding amino acid codons was found. To obtain this correlation all the codons had to be arranged in a closed ring in which the consecutive codons were connected by one-step mutational changes. One-step mutations appeared as a regular series: 2,3,3,3,1,3,3,3,1,3,3,3,1,3,3,3,2,3,3,3. (the numbers denote a codon position in which a change took place). There were three such 'one-step mutation periods' in the ring, each containing 20 codons (in each block of 16 codons with A, U and C, in the central position and 4 codons containing G in the central position). The end of the third period (UG) and the beginning of the first period were bridged by the four codons of glycine with G in the second position. The values of delta G++ change similarly in each period, increasing upon approaching Lys, Pro, and Ile. The periodical relation between the chemical reactivities of the coded amino acids (reflected by delta G++s) and the structure of their codons could be of importance for the origin of the genetic code i.e. for selection of proper codons for the definite amino acids.

Amino Acid Sequence↗

Origin of the genetic code: a testable hypothesis based on tRNA structure, sequence, and kinetic proofreading.

We hypothesize that the origin of the genetic code is associated with the structure of the tRNA that existed in primal cells. The sequences of modern tRNA contain correlations which can be understood as "fossil" evidence of the secondary structure of primal tRNA. Kinetic proofreading through diffusion can amplify a low level of intrinsic selectivity of tRNA for its amino acid. Experimental tests of the theory are suggested.

Amino Acyl-tRNA Synthetases↗