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Using the simulated annealing technique we re-examine the role played by the minimization of the physicochemical distances between amino acids during the origin of the organization of the genetic code. The results are discussed in the context of the various hypotheses proposed to explain how amino acids were allocated in the genetic code.
There are a few instances in which positive Darwinian selection has been convincingly demonstrated at the molecular level. In this study, we present a novel test for detecting excess of radical amino-acid replacements. Such excess is usually indicative of positive Darwinian selection, but may also be due to relaxed functional constraints or model misspecification. In our test, each amino-acid replacement is characterized in terms of a physicochemical distance, i.e., the degree of dissimilarity between the exchanged amino-acid residues. By using phylogenetic trees based on protein sequences, our test identifies statistically significant deviations of the mean physicochemical distance from the random expectation, either along a taxonomic lineage or across a subtree. The mean inferred distance is calculated as the average physicochemical distance over all possible ancestral sequence reconstructions weighted by their likelihood. Our method substantially improves over previous approaches by taking into account the stochastic process, tree phylogeny, among-site rate variation, and alternative ancestral reconstructions. We provide a fast linear time algorithm for applying this test to all branches and all subtrees of a given phylogenetic tree. We validate this approach by applying it to two well-studied datasets: the MHC class I glycoproteins serving as a positive control, and the house-keeping gene carbonic anhydrase I serving as a negative control.
Models of amino acid substitution were developed and compared using maximum likelihood. Two kinds of models are considered. "Empirical" models do not explicitly consider factors that shape protein evolution, but attempt to summarize the substitution pattern from large quantities of real data. "Mechanistic" models are formulated at the codon level and separate mutational biases at the nucleotide level from selective constraints at the amino acid level. They account for features of sequence evolution, such as transition-transversion bias and base or codon frequency biases, and make use of physicochemical distances between amino acids to specify nonsynonymous substitution rates. A general approach is presented that transforms a Markov model of codon substitution into a model of amino acid replacement. Protein sequences from the entire mitochondrial genomes of 20 mammalian species were analyzed using different models. The mechanistic models were found to fit the data better than empirical models derived from large databases. Both the mutational distance between amino acids (determined by the genetic code and mutational biases such as the transition-transversion bias) and the physicochemical distance are found to have strong effects on amino acid substitution rates. A significant proportion of amino acid substitutions appeared to have involved more than one codon position, indicating that nucleotide substitutions at neighboring sites may be correlated. Rates of amino acid substitution were found to be highly variable among sites.
The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous ρ-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as ρ moves Q6→H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at α=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p≤10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.
How to incorporate the sequence order effect is a key and logical step for improving the prediction quality of protein subcellular location, but meanwhile it is a very difficult problem as well. This is because the number of possible sequence order patterns in proteins is extremely large, which has posed a formidable barrier to construct an effective training data set for statistical treatment based on the current knowledge. That is why most of the existing prediction algorithms are operated based on the amino-acid composition alone. In this paper, based on the physicochemical distance between amino acids, a set of sequence-order-coupling numbers was introduced to reflect the sequence order effect, or in a rigorous term, the quasi-sequence-order effect. Furthermore, the covariant discriminant algorithm by Chou and Elrod (Protein Eng. 12, 107-118, 1999) developed recently was augmented to allow the prediction performed by using the input of both the sequence-order-coupling numbers and amino-acid composition. A remarkable improvement was observed in the prediction quality using the augmented covariant discriminant algorithm. The approach described here represents one promising step forward in the efforts of incorporating sequence order effect in protein subcellular location prediction. It is anticipated that the current approach may also have a series of impacts on the prediction of other protein features by statistical approaches.
A codon-based model for the evolution of protein-coding DNA sequences is presented for use in phylogenetic estimation. A Markov process is used to describe substitutions between codons. Transition/transversion rate bias and codon usage bias are allowed in the model, and selective restraints at the protein level are accommodated using physicochemical distances between the amino acids coded for by the codons. Analyses of two data sets suggest that the new codon-based model can provide a better fit to data than can nucleotide-based models and can produce more reliable estimates of certain biologically important measures such as the transition/transversion rate ratio and the synonymous/nonsynonymous substitution rate ratio.
In earlier distance geometry related three-dimensional quantitative structure-activity relationships (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1984, 27, 901) the interactions of the ligand atom or group with the receptor site were evaluated empirically by using mathematical optimization techniques, without considering their physicochemical properties. In the present work we show how to use various physicochemical parameters in our three-dimensional receptor mapping. We have developed a model for E. coli DHFR using the inhibition data of 25 pyrimidines and 14 triazines. It gave a correlation coefficient of 0.893 and standard deviation of 0.530. It successfully predicted the binding data of five pyrimidines and five triazines.
This paper developed the Edge degree-Distance Index (EDI) and Sum of edges (S(e)) based on the edge and distance of molecular graph. This set of topological indices, EDI, S(e) combined with VDI, OEI, and RDI proposed in our previous paper can characterize the molecular structures of diverse hydrocarbons well. The regression analyses against nine physicochemical properties, such as boiling points (Bp), critical properties (Tc, Pc, Vc), heat capacities (Cp), and so on, of 1038 diverse hydrocarbons were investigated, and good correlations were obtained.
A novel set of molecular descriptors suitable for use in quantitative structure-activity relationships and related methods is described. These descriptors are a smooth and interpretable representation of atomic physicochemical property values and intramolecular atom pair distances. Distance atomic physicochemical parameter energy relationships (DAPPER), a novel structure-activity relationship (QSAR) method using these descriptors, is validated on standard datasets.
HLA evolutionary divergence (HED), a continuous metric quantifying the differences between each amino acid of two homologous HLA alleles, reflects the importance of the immunopeptidome presented to T lymphocytes. It has been associated with rejection after liver transplantation. This retrospective cohort study aimed to analyse the potential effect of donor or recipient HED on liver transplant rejection in a new series of patients transplanted during childhood and followed in adulthood. The study included 120 children who had been transplanted between 1991 and 2010 and were followed by routine biopsies and histological evaluations with a median of 14.1 years post-LT. Liver biopsies were performed routinely 1, 5, 10 and 20 years after transplantation and in the event of liver dysfunction. HED was calculated using the physicochemical Grantham distance for donor and recipient Class I (HLA-A, -B, -C) and Class II (HLA-DRB1, -DQB1) alleles. The influence of HED on rejection was analysed using inverse probability weighting (IPW) and target trial emulation using the g method. Based on the IPW score, donor HED class I was correlated with the occurrence of late (> 90 days) rejection (HR, 1.19, 95% CI: 1.01-1.40) independently of HLA mismatches, donor age and initial induction. The emulated target trial confirmed that donor HED Class I has a causal effect on liver graft rejection and this relationship was observed long-term.
The allocation of codons in the genetic code makes possible a moderate minimization of the chemical distances between pairs of neighboring amino acids in the code. However, the code is neither a global nor a local optimum with respect to distance minimization. These findings do not support the physicochemical postulate that distance minimization was a major factor shaping the evolution of the genetic code. They agree with the coevolution theory, which proposes that genetic code evolution was predominantly determined by the concession of codons from precursor to product amino acids in an expansion of the code to accommodate new varieties of amino acids, with distance minimization playing a subsidiary role in deciding the choice of codons to be acquired by the product amino acids from the codon domains of the precursor amino acids.
Starting from the four DNA bases order in the Boolean lattice, a novel Lie Algebra of the genetic code is proposed. Here, the main partitions of the genetic code table were obtained as equivalent classes of quotient spaces of the genetic code vector space over the Galois field of the four DNA bases. The new algebraic structure shows strong connections among algebraic relationships, codon assignments and physicochemical properties of amino acids. Moreover, a distance defined between codons expresses a physicochemical meaning. It was also noticed that the distance between wild type and mutant codons tends to be small in mutational variants of four genes: human phenylalanine hydroxylase, human beta-globin, HIV-1 protease and HIV-1 reverse transcriptase. These results strongly suggest that deterministic rules in genetic code origin must be involved.
A rational method is presented for the selection of substituents to be introduced into a benzenoid ring system of a biologically active compound in order to a defined physicochemical parameter space. The method, which may be readily programmed for use on a computer, relies on maintaining a minimum distance between compounds in the multidimensional physicochemical parameter space. The series of compounds produced will then have a well-spread set of minimally correlated physicochemical parameter values and could thus be used for the reliable correlation of the variation in the biological activities of the members of the series with changes in these physicochemical parameters. Some examples of the use of the present method under various conditions are given, and it is compared with alternatives in the literature.
The influence of the suppository base on the in-vitro release of isoconazole nitrate was studied by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. Vaginal suppository formulations containing 25 mg isoconazole nitrate for local treatment of vaginitis were prepared by a fusion method, using different hydrophilic and lypophilic suppository bases (PEG 6000, PEG 4000, PEG 1500, Witepsol H15, Novata BD and Cremao). In-vitro release rates were examined by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. In the physicochemical investigations the pH indicators (pH 1-14) erythrosin B, thymol blue, bromocresol green, chlorophenol red, phenol red, and alkali blue were added to agar gels. The discs were placed onto the agar gels and 21 h later, the coloured zone diameters were measured. In the microbiological investigations, the discs were put on the inoculated plates with the suspension of Candida albicans (Institute Pasteur 628). The inoculated plates were incubated at 37 degrees C for 3 days, then the diameters of inhibition zones were measured. In the dissolution investigations release rates were in the order PEG 6000 > PEG 4000 > PEG 1500 > > Witepsol H15 > Cremao > Novata BD. The diffusion distance of isoconazole nitrate in the physicochemical investigation was in the order polyethylene glycols > Witepsol H15 > Novata BD. In the microbiological studies release rates were found with polyethylene glycols > Witepsol H15 > Novata BD > Cremao. The findings in the in-vitro studies suggested that polyethylene glycols are suitable bases for vaginal suppositories.
Messenger RNA sequences often have to preserve functional secondary structure elements in addition to coding for proteins. We present a statistical analysis of retroviral mRNA which supports the hypothesis that the natural genetic code is adapted to such complementary coding. These sequences are still able to explore efficiently the space of possible proteins by point mutations. This is borne out by the observation that, in stem regions of retroviral mRNA foldings, silent mutations on one strand are preferentially accompanied by conservative mutations on the other. Distances between amino acids based on physicochemical properties are used to quantify the conservation of protein function under the constraint of maintained RNA secondary structure. We find that preservation of RNA secondary structure by compensatory mutations is evolutionary compatible with the efficient search for new variants on the protein level.
Despite 30 years of study on Na+/H+ exchange, the molecular mechanisms of antiport remain obscure. Most challenging, the identity of amino acids involved in binding transported cations is still unknown. We review data examining the identity of residues that are involved in cation binding and translocation of prokaryotic and eukaryotic Na+/H+ antiporters. Several polar residues specifically distributed within or immediately adjacent to membrane spanning regions are implicated as being important. These key amino acids are conserved in prokaryotes and in some lower eukaryotic forms of the Na+/ H+ antiporter, despite their being dispersed throughout the protein and despite an overall low similarity in the linear sequence of these Na+/H+ antiporters. We suggest that this conservation of isolated residues (together with distances between them) reflects a general physicochemical mechanism of cation binding by exchangers. The binding could be based on coordination of the substrate cation by a crown ether-like cluster of polar atomic groups amino acids, as has been hypothesized by Boyer. Traditional screening for the extended, highly conserved linear protein sequences might not be applicable when searching for functional domains of ion transporters. Three-dimensional constellations of polar residues (3D-motifs) may be evolutionary conserved rather than linear primary sequence.
Correlations between placental size and fetal mass during gestation fail to account for changes in composition that accompany placental growth and maturation. This study uses stereological data on the sizes of different tissue compartments in human placentas from 10 weeks of gestation to term and relates them to placental volume and to fetal mass by means of allometric analysis. In addition, tissue dimensions are used to calculate a physiological transport measure (diffusive conductance) for the villous membrane. Histological sections randomly sampled from placentas and analysed stereologically provided estimates of structural quantities (volumes, exchange surface areas, lengths, numbers of nuclei, diffusion distances). These data were combined with a physicochemical quantity (Krogh's diffusion coefficient) in order to estimate oxygen diffusive conductances for the villous membrane and its two components (trophoblast and stroma). Allometric relationships between these quantities and placental volume or fetal mass were obtained by linear regression analyses after log-transformation. Placental tissues had different growth trajectories: most grew more rapidly than placental volume and all grew more slowly than fetal mass. Diffusion distances were inversely related to placental and fetal size. Differential growth impacted on diffusive conductances, which, again, did not improve commensurately with placental volume but did match exactly growth of the fetus. Findings show that successful integration between supply and demand can be achieved by differential tissue growth. Allometric analysis of results from recent studies on the murine placenta suggest further that diffusive conductances may also be matched to fetal mass during gestation and to fetal mass at term across species.
An alternative approach is reported to compute property fields based on similarity indices of drug molecules that have been brought into a common alignment. The fields of different physicochemical properties use a Gaussian-type distance dependence, and no singularities occur at the atomic positions. Accordingly, no arbitrary definitions of cutoff limits and deficiencies due to different slopes of the fields are encountered. The fields are evaluated by a PLS analysis similar to the CoMFA formalism. Two data sets of steroids binding to the corticosteroid-binding-globulin and thermolysin inhibitors were analyzed in terms of the conventional CoMFA method (Lennard-Jones and Coulomb potential fields) and the new comparative molecular similarity indices analysis (CoMSIA). Models of comparative statistical significance were obtained. Field contribution maps were produced for the different models. Due to cutoff settings in the CoMFA fields and the steepness of the potentials close to the molecular surface, the CoMFA maps are often rather fragmentary and not contiguously connected. This makes their interpretation difficult. The maps obtained by the new CoMSIA approach are superior and easier to interpret. Whereas the CoMFA maps denote regions apart from the molecules where interactions with a putative environment are to be expected, the CoMSIA maps highlight those regions within the area occupied by the ligand skeletons that require a particular physicochemical property important for activity. This is a more significant guide to trace the features that really matter especially with respect to the design of novel compounds.