Hydropathic anti-complementarity of amino acids based on the genetic code

An interesting pattern in the genetic code has been discovered. Codons for hydrophilic and hydrophobic amino acids on one strand of DNA are complemented by codons for hydrophobic and hydrophilic amino acids on the other DNA strand, respectively. The average tendency of codons for "uncharged" (slightly hydrophilic) amino acids is to be complemented by codons for "uncharged" amino acids.     

A genetic code Boolean structure. I. The meaning of Boolean deductions

This paper proposes a genetic code Boolean structure derived from hydrogen bond numbers and chemical types of bases, purines and pyrimidines. It shows that in such Boolean structure, deductions comprise physico-chemical meaning. In particular, codons with adenine as a second base coding to hydrophilic amino acids are not deductible from codons with uracil in the same position, which code to hydrophobic amino acids. Boolean deductions could help us describe the gene evolution process. For instance, most of the reported mutations that confer drug resistance to the HIV protease gene correspond to deductions. What is more, in the human beta-globin gene a similar situation appears where most of the single codon mutations correspond to Boolean deductions from the respective wild-type codon.     

Complementary hydropathy and the evolution of interacting polypeptides

Summary It has been shown that codons coding for strongly hydrophilic amino acids are complemented by codons that code for strongly hydrophobic ones, leading to a hypothesis stating that peptides thus encoded should interact. Though the principle has been validated in a number of experimental models, its general applicability has been questioned. I have discussed this principle, showing that the correlation between coding and noncoding strand amino acids was maintained, indeed slightly improved, when weighted averages based on codon usage tables were used to determine noncoding strand amino acid hydropathies. The coding capacity of the noncoding strand and its content of open reading frames were also discussed. Another point of contention that was afforded further clarification is the chemical plausibility of interactions between hydrophobic and hydrophilic amino acids implicit in this concept. The extension of complementary domains was also dealt with. Finally, I have discussed what I called the evolutionary drift of primary structure, and I showed as an example that though nucleotide sequences coding for the substance K receptor bear little resemblance to the inverse complement of that which codes for the SK peptide, a peptide spanning residues 130–139 is hydropathically very similar to that predicted from such an inverse complement.     

Characterization of the N-linked high-mannose oligosaccharides of the insulin pro-receptor and mature insulin receptor subunits.

An interesting pattern in the genetic code was reported previously [Blalock & Smith (1984) Biochem. Biophys. Res. Commun. 121, 203-207]. In the 5'-to-3' direction, codons for hydrophilic and hydrophobic amino acids are generally complemented by codons for hydrophobic and hydrophilic amino acids respectively. The average tendency of codons for 'unchanged' (slightly hydrophilic) amino acids was to be complemented by codons for 'unchanged' amino acids. We now show that the same pattern results when the complementary codon is read in the 3'-to-5' direction. This pattern is further shown to result in the interaction of peptides specified by complementary RNAs regardless of whether the amino acids are assigned in the 5'-to-3' or the 3'-to-5' direction. Here we demonstrate that peptides specified by complementary RNAs bind to each other with specificity and high affinity.     

Second codon positions of genes and the secondary structures of proteins. Relationships and implications for the origin of the genetic code

The nucleotide frequencies in the second codon positions of genes are remarkably different for the coding regions that correspond to different secondary structures in the encoded proteins, namely, helix, beta-strand and aperiodic structures. Indeed, hydrophobic and hydrophilic amino acids are encoded by codons having U or A, respectively, in their second position. Moreover, the beta-strand structure is strongly hydrophobic, while aperiodic structures contain more hydrophilic amino acids. The relationship between nucleotide frequencies and protein secondary structures is associated not only with the physico-chemical properties of these structures but also with the organisation of the genetic code. In fact, this organisation seems to have evolved so as to preserve the secondary structures of proteins by preventing deleterious amino acid substitutions that could modify the physico-chemical properties required for an optimal structure.     

Role of mutational bias and natural selection on genome-wide nucleotide bias in prokaryotic organisms

Correlations between genomic GC contents and amino acid frequencies were studied in the homologous sequences of 12 eubacterial genomes. Results show that amino acids encoded by GC-rich codons increases significantly with genomic GC contents, whereas opposite trend was observed in case of amino acids encoded by GC-poor codons. Further studies show all the amino acids do not change in the predicted direction according to their genomic GC pressure, suggesting that protein evolution is not entirely dictated by their nucleotide frequencies. Amino acid substitution matrix calculated among hydrophobic, amphipathic and hydrophilic amino acid groups' shows that amphipathic and hydrophilic amino acids are more frequently substituted by hydrophobic amino acids than from hydrophobic to hydrophilic or amphipathic amino acids. This indicates that nucleotide bias induces a directional changes in proteome composition in such a way that underwent strong changes in hydropathy values. In fact, significant increases in hydrophobicity values have also been observed with the increase of genomic GC contents. Correlations between GC contents and amino acid compositions in three different predicted protein secondary structures show that hydropathy values increases significantly with GC contents in aperiodic and helix structures whereas strand structure remains insensitive with the genomic GC levels. The relative importance of mutation and selection on the evolution of proteins have been discussed on the basis of these results.     

Distinct character in hydrophobicity of amino acid compositions of mitochondrial proteins

A compact mitochondrial gene contains all essential information about the synthesis of mitochondrial proteins which play their roles in a small compartment of the mitochondrium. Almost no noncoding regions have been found through the gene, but a necessary set of tRNAs for the 20 amino acids is provided for biosynthesis, some of them coding different amino acids from those in a usual cell. Since the gene is so compact that the produced proteins would have some characteristic aspects for the mitochondrium, amino acid compositions of mitochondrial proteins (mt-proteins) were examined in the 20-dimensional composition space. The results show that compositions of proteins translated from the mitochondrial genes have a distinct character having more hydrophobic content than others, which is illustrated by a clustered distribution in the multidimensional composition space. The cluster is located at the tail edge of the global distribution pattern of a Gaussian shape for other various kinds of proteins in the space. The mt-proteins are rich in hydrophobic amino acids as is a membrane protein, but are different from other membrane proteins in a lesser content of Val. A good correlation found between the base and amino acid compositions for the mitochondria was examined in comparison to those of organisms such as thermophilic bacterium having an extreme G-C-rich base composition.     

Comparative study of translation termination sites and release factors (RF1 and RF2) in procaryotes

Translation termination is catalyzed by release factors that recognize stop codons. However, previous works have shown that in some bacteria, the termination process also involves bases around stop codons. Recently, Ito et al. analyzed release factors and identified the amino acids therein that recognize stop codons. However, the amino acids that recognize bases around stop codons remain unclear. To identify the candidate amino acids that recognize the bases around stop codons, we aligned the protein sequences of the release factors of various bacteria and searched for amino acids that were conserved specifically in the sequence of bacteria that seemed to regulate translation termination by bases around stop codons. As a result, species having several highly conserved residues in RF1 and RF2 showed positive correlations between their codon usage bias and conservation of the bases around the stop codons. In addition, some of the residues were located very close to the SPF motif, which deciphers stop codons. These results suggest that these conserved amino acids enable the release factors to recognize the bases around the stop codons. Present address (Y. Ozawa): Tokyo Research Laboratory, IBM Japan, Ltd., 1623-14 Shimotsuruma, Yamato-shi, Kanagawa 242-8502, Japan     

From interstellar amino acids to prebiotic catalytic peptides: a review

Amino acids were most likely available on the primitive Earth, produced in the primitive atmosphere or in hydrothermal vents. Import of extraterrestrial amino acids may have represented the major supply, as suggested by micrometeorite collections and simulation experiments in space and in the laboratory. Selective condensation of amino acids in water has been achieved via N-carboxy anydrides. Homochiral peptides with an alternating sequence of hydrophobic and hydrophilic amino acids adopt stereoselective and thermostable beta-pleated sheet structures. Some of the homochiral beta-sheets strongly accelerate the hydrolysis of oligoribonucleotides. The beta-sheet-forming peptides have also been shown to protect their amino acids from racemization. Even if peptides are not able to self-replicate, i.e., to replicate a complete sequence from the mixture of amino acids, the accumulation of chemically active peptides on the primitive Earth appears plausible via thermostable and stereoselective beta-sheets made of alternating sequences.     

Quantum mechanical model for information transfer from DNA to protein

A model for the information transfer from DNA to protein using quantum information and computation techniques is presented. DNA is modeled as the sender and proteins are modeled as the receiver of this information. On the DNA side, a 64-dimensional Hilbert space is used to describe the information stored in DNA triplets (codons). A Hamiltonian matrix is constructed for this space, using the 64 possible codons as base states. The eigenvalues of this matrix are not degenerate. The genetic code is degenerate and proteins comprise only 20 different amino acids. Since information is conserved, the information on the protein side is also described by a 64-dimensional Hilbert space, but the eigenvalues of the corresponding Hamiltonian matrix are degenerate. Each amino acid is described by a Hilbert subspace. This change in Hilbert space structure reflects the nature of the processes involved in information transfer from DNA to protein.     

Polarity and hydropathic properties of natural amino acids

A new classification of amino acids according to their polarity and symmetric location in the spatial structure of the genetic code is suggested. The polar amino acids are: R, S (codons AGC and AGU), K, N, Q, H, W, C, Y, G, E, D; apolar ones are: T, M, I, P, L, S (codons UCN). Polar and apolar amino acids are grouped into three families whose members possess complementarity with respect to the symmetric structure of the genetic code. Interaction of these complementary polar and apolar amino acids encodes formation of the space structures and ligand-receptor complexes of proteins. Correlation between the polar and hydropathic properties of amino acids is investigated. Normalization of 38 hydrophobicity scales of natural amino acids is carried out. A discrepancy between structures of polar/hydrophilic and apolar/hydrophobic groups of amino acids is demonstrated. According to the signature principle this discrepancy is due to different properties of amino acid side radicals which, in turn, depend on the second component of the reaction and on environmental conditions.     

Genetic Code Evolution Started with the Incorporation of Glycine,Followed by Other Small Hydrophilic Amino Acids

We propose that glycine was the first amino acid to be incorporated into the genetic code, followed by serine, aspartic and/or glutamic acid—small hydrophilic amino acids that all have codons in the bottom right-hand corner of the standard genetic code table. Because primordial ribosomal synthesis is presumed to have been rudimentary, this stage would have been characterized by the synthesis of short, water-soluble peptides, the first of which would have comprised polyglycine. Evolution of the code is proposed to have occurred by the duplication and mutation of tRNA sequences, which produced a radiation of codon assignment outwards from the bottom right-hand corner. As a result of this expansion, we propose a trend from small hydrophilic to hydrophobic amino acids, with selection for longer polypeptides requiring a hydrophobic core for folding and stability driving the incorporation of hydrophobic amino acids into the code.     

Nonrandom Intragenic Variations in Patterns of Codon Bias Implicate a Sequential Interplay Between Transitional Genetic Drift and Functional Amino Acid Selection

Although most codon third bases appear to be functionless, the synonymous codons so defined exhibit a strikingly nonrandom distribution (codon bias) within human and other genes. To examine this phenomenon further, we generated a database of DNA sequences encoding human transmembrane cell-surface receptor proteins. Using this database we show here that the guanine and cytosine content of codon third bases (GC3) varies intragenically with the nature of the specified receptor domains (transmembrane > extracellular > intracellular domains; p < 0.001), the phenotype of the encoded amino acids (hydrophobic > hydrophilic > neutral amino acids; p < 0.001), and the receptor affiliation of the transmembrane domain superfamily (G-protein- coupled receptors > receptor tyrosine kinases; p < 0.001). Within gene regions specifying transmembrane domains, GC3 declines as domain functionality becomes redundant with increasing hydrophobicity (p < 0.001). Codons containing the second-base cytosine (XCZ, which encodes neutral amino acids) are selectively depleted of third-base adenine content (A3: XCA codons) when encoding transmembrane domain residues, consistent with positive selection for transitional mutation of XCG to XTG (which encodes hydrophobic amino acids) rather than to the synonymous XCA. Supporting this XCG XTG mechanism of codon bias, the G3:A3 ratio of codons specifying the transmembrane amino acid glycine (GGZ) is intermediate between that of its functional homolog alanine (GCZ) and that of hydrophobic valine (GTZ), even though the C3:T3 ratios are similar. Conversely, nearest-neighbor analysis of third bases 5 to codons specifying valine and leucine (CTZ) confirms a significant difference in C3:T3 but not G3:A3 ratios (i.e., C3/G1 T3/G1 > C3/A1; p < 0.001), consistent with the functionally advantageous retention of hydrophobic residues. These data raise the possibility that patterns of intragenic codon bias reflect a balance between negative and positive selection, suggesting in turn that analysis of codon third-base usage may help to predict the functional significance of encoded products. Supplementary information: Current address: (K. Lin) College of Life Sciences, Beijing Normal University, Beijing 100875, China     

A Model of Proto-Anti-Codon RNA Enzymes Requiring l-Amino Acid Homochirality

All living organisms encode the 20 natural amino acid units of polypeptides using a universal scheme of triplet nucleotide "codons". Disparate features of this codon scheme are potentially informative of early molecular evolution: (i) the absence of any codons for D-amino acids; (ii) the odd combination of alternate codon patterns for some amino acids; (iii) the confinement of synonymous positions to a codon's third nucleotide; (iv) the use of 20 specific amino acids rather than a number closer to the full coding potential of 64; and (v) the evolutionary relationship of patterns in stop codons to amino acid codons. Here I propose a model for an ancestral proto-anti-codon RNA (pacRNA) auto-aminoacylation system and show that pacRNAs would naturally manifest features of the codon table. I show that pacRNAs could implement all the steps for auto-aminoacylation: amino acid coordination, intermediate activation of the amino acid by the 5'-end of the pacRNA, and 3'-aminoacylation of the pacRNA. The anti-codon cradles of pacRNAs would have been able to recognize and coordinate only a small number of L-amino acids via hydrogen bonding. A need for proper spatial coordination would have limited the number of chargeable amino acids for all anti-codon sequences, in addition to making some anti-codon sequences unsuitable. Thus, the pacRNA model implies that the idiosyncrasies of the anti-codon table and L-amino acid homochirality co-evolved during a single evolutionary period. These results further imply that early life consisted of an aminoacylated RNA world with a richer enzymatic potential than ribonucleotides alone.     

Differential effect of amino acid residues on the stability of double helices formed from polyribonucleotides and its possible relation to the evolution of the genetic code

The interaction of amino acid residues with polyribonucleotides was characterized by measurements of melting temperatures (tm) for poly(A).poly(U) and poly(I).poly(C) as functions of the concentrations of various amino acid amides. The amides of hydrophilic amino acids lead to a continuous increase of tm with increasing concentration, whereas amides of hydrophobic amino acids induce a decrease of tm at low concentrations (approximately 1 mM) followed by an increase at higher concentrations. Analysis of the data by a simple site model provides the affinity of each ligand for the double helix relative to that for the single strands. This parameter decreases in the order Ala greater than Gly greater than Ser greater than Asn greater than Pro greater than Met, Val greater than Ile, Leu for poly(A).poly(U) and Ala, Gly, Ser greater than Asn greater than Pro greater than Val greater than Ile, Met, Leu for poly(I).poly(C). The special effects of hydrophobic amino acids may be related to the similarity of the codons for these amino acids. A simple model for assignment of codons to amino acids is proposed.     

三联体密码子在mRNA二级结构中的分布

对编码成熟肽的ｍＲＮＡ二级结构的分析显示,每个密码子在ｍＲＮＡ二级结构中的位置有一定的倾向性,这种倾向性似乎与相应氨基酸的构象性质相一致。大多数编码疏水氨基酸的密码子位于ｍＲＮＡ二级结构中较稳定的茎区;反之,大多数编码亲水氨基酸的密码子位于柔性的环区。这个结果支持了最近得到的关于ｍＲＮＡ与蛋白质之间存在丰三维结构信息传递的结论。     

Primordial Coding of Amino Acids by Adsorbed Purine Bases

Scanning tunneling microscopy and chromatography experiments exploring the potential templating properties of nucleic acid bases adsorbed to the surface of crystalline graphite, revealed that the interactions of amino acids with the bare crystal surface are significantly modulated by the prior adsorption of adenine and hypoxanthine. These bases are the coding elements of a putative purine-only genetic alphabet and the observed effects are different for each of the bases. Such mapping between bases and amino acids provides a coding mechanism. These observations demonstrate that a simple pre-RNA amino acid discrimination mechanism could have existed on the prebiotic Earth providing critical functionality for the origin of life.     

Intrinsic disorder in protein sense‐antisense recognition

In addition to the well‐established sense‐antisense complementarity abundantly present in the nucleic acid world and serving as a basic principle of the specific double‐helical structure of DNA, production of mRNA, and genetic code‐based biosynthesis of proteins, sense‐antisense complementarity is also present in proteins, where sense and antisense peptides were shown to interact with each other with increased probability. In nucleic acids, sense‐antisense complementarity is achieved via the Watson‐Crick complementarity of the base pairs or nucleotide pairing. In proteins, the complementarity between sense and antisense peptides depends on a specific hydropathic pattern, where codons for hydrophilic and hydrophobic amino acids in a sense peptide are complemented by the codons for hydrophobic and hydrophilic amino acids in its antisense counterpart. We are showing here that in addition to this pattern of the complementary hydrophobicity, sense and antisense peptides are characterized by the complementary order‐disorder patterns and show complementarity in sequence distribution of their disorder‐based interaction sites. We also discuss how this order‐disorder complementarity can be related to protein evolution.