Martynas Yčas

On earlier states of the biochemical system.

Similarities between essential enzymes indicate homology and therefore origin from a smaller number of ancestral genes, but there are also indications that the immediately preceding biochemical system was of about the same complexity as the present one. It is argued that to maintain function with a smaller number of enzymes, earlier enzymes must have been less specific, catalyzing classes of reactions. Lower specificity also resulted in ambiguous translation, each cistron producing a family of related proteins. Though individual protein molecules need not have been less specific, each family as a whole functioned as a catalyst of lower specificity. The number of kinds of amino acids incorporated into proteins may have been larger than at present. The evidence supporting this, some of its implications, and the kinds of additional data that would be useful in such problems are discussed.

On the computation of the tertiary structure of globular proteins

Abstract A method is presented to compute the approximate locations of α carbon atoms of proteins using experimentally obtainable information. This information consists of distances between nearest neighbor α carbon atoms, locations of SS bonds, primary sequence of amino acids as reflected by hydrophobic and hydrophylic residues and the assumption of globularity. The method permits the reconstruction of structure similar to the real ones, and is readily extendable to compute structures more accurately by incorporating additional information.

De novo origin of periodic proteins.

SummarySilk fibroin, collagen, “freezing point depressing” glycoproteins, keratin and protamines have periodic amino acid sequences which are unlikely to have arisen by amino acid replacements and internal duplications of non-periodic DNA. Evidence here discussed suggests that such proteins arise by a single evolutionary event, an iterativede novo synthesis of DNA.

The error catastrophe hypothesis with reference to aging and the evolution of the protein synthesizing machinery

A theory of the propagation of errors in the system of enzymes translating genetic information into proteins is presented. The formulation, which is non-statistical, makes it possible to determine the quantities of individual components of a system at any time. It is shown that depending on the initial conditions and on the effects of amino acid substitutions on enzymic activity, error catastrophe, stable states containing error, extinction of some amino acids, or evolution toward less ambiguous translation can occur. The results speak against the error catastrophe hypothesis of aging. The theory also provides a method to study the behavior of any self-replicating systems which might be surmised to have existed at earlier stages of the evolution of life.

A method for calculating codon frequencies in DNA

Abstract Since the biological code is degenerate, the frequencies of occurrence of codons are not uniquely determined by the amino acid frequencies in proteins. A method of calculating these codon frequencies is presented here. It is assumed that the anti-sense strand of DNA consists of a sequence of codons randomly juxtapositioned, as is indicated by the statistically random sequence of amino acids in proteins. Using experimental data on average frequencies of amino acids in proteins, and on nearestneighbor frequencies and frequencies of pyrimidine runs flanked by purines in DNA, it is possible to write equations expressing constraints on the codon frequencies. Using the existing data, the frequencies of 20 codons and 24 linear combinations of codons can be calculated. This is done using a newly developed optimization procedure. The type of data that would be needed to calculate frequencies of all 64 codons is described. The method has been tested on hypothetical DNA molecules. The solutions are rather insensitive to errors in the estimates of amino acid frequencies but are very sensitive to errors in the estimate of doublet frequencies and pyrimidine runs. Since the equations are of degree up to five, the solutions are not unique. It is found, however, that “acceptable” solutions (those not containing negative values for the codon frequencies) do not seem to be numerous. Since most of the degeneracy of the genetic code is at the third place, for a given set of amino acid frequencies certain percentages of A, C, G and T are required for the first two places. The initial guess used for the iterative procedure is obtained by assuming that the percentage of nucleotides left for the third place is distributed randomly. A random perturbation of the initial guess of up to 10% yields the same solution. The method has been used to calculate codon frequencies in the DNA of three vertebrates, one plant (yeast) and seven bacteria. It is found that, in general, all the codons for a given amino acid are not used equally, and the relative frequencies vary with the species.

A model for binary logic in biochemical systems

Abstract A model system involving a series of enzyme reactions, some of which display a sigmoid relationship between activity and substrate concentration, is discussed as a possible basis for binary logic in biochemical systems. Under the conditions described, a small change in the concentration of an initial substrate changes the activity of a terminal enzyme from nearly zero to nearly maximal activity, thus approximating a step-function or an on-off switch. Although the mechanistic basis for the sigmoid relationship is not limited to the allosteric model, allosterism is used for purposes of assigning a possible physical meaning to the parameters used in a sample calculation. The possible generation of square wave functions and timed pulses from the model is discussed.

The error catastrophe hypothesis and aging.

SummaryA theory of the propagation of errors in the system of enzymes translating genetic information into proteins developed earlier is extended to include errors at the transcription level. The theory is compared to other statistical theories. The properties are defined of the protein synthesizing machineries, especially those of the erroneous enzymes, which give catastrophe, stable self-replication containing errors, recovery from errors, etc. Experimental data are analyzed in light of the theory to determine the validity of the error catastrophe hypothesis of aging.

Replacement of amino acids in proteins

Abstract Some consequences of the hypothesis that ribonucleic acid codes amino acid sequences with a coding ratio of one are discussed. The hypothesis predicts certain limitations on amino acid replacements in proteins as a result of mutation. Available evidence is reviewed and found to conform with prediction.

Computing tertiary structures of proteins

Using only data on sequence, a method of computing a low-resolution tertiary structure of a protein is described. The steps are: (a) Estimate the distances of individual residues from the centroid of the molecule, using data on hydrophobicity and additional geometrical constraints. (b) Using these distances, construct a two-valued matrix whose elements, the distances between residues, are greater or less thanR, the radius of the molecule. (c) Optimize to obtain a three-dimensional structure. This procedure requires modest computing facilities and is applicable to proteins with 164 residues and presumably more. It produces structures withr (correlation between inter-residue distances in the computed and native structures) between 0.5 and 0.7. Furthermore, correct inference of two or three long-range contacts suffices to yield structures withr values of 0.8–0.9. Because segments forming parallel or antiparallel folding structures intersect the radius vector at similar angles, from centroidal point distances it is possible to infer some of these long-range contacts by an elaboration of the procedure used to construct the input matrix. A criterion is also described which can be used to determine the quality of a proposed input matrix even when the native structure is not known.

Codons and Hypercycles

Several hypotheses on the origin of codon assignments imply that the present protein synthesizing machinery was already in place when the assignments were made. These are examined by computer modeling. The results do not suggest that assignments were optimized for resistance to reading and mutation errors, nor that the assignments are random. It is improbable that the number of species of amino acids increased in the course of evolution. An originally ambiguous dictionary is likely to have been subject to error catastrophe and is improbable. A relation between amino acid properties and their codons exists, and suggests that the codon assignments were established at the time of origin of the hypercycle, i.e. a system of aminoacyl synthetases which attaches amino acids to tRNA, and before the present protein synthesizing machinery was in place. The origin of a hypercycle is only possible if the system began with components which were catalytically active even when they did not form a self-replicating system. A model of such a system is proposed.