Semih Erhan

Amino-acid neighborhood relationships in proteins. Breakdown of amino-acid sequences into overlapping doublets, triplets and quadruplets

A method has been developed which allows the breakdown of an amino-acid sequence of proteins into overlapping di-, tripeptides, etc. The frequency of their distribution provides very convincing evidence that these sequences are non-random. These peptides have been demonstrated to be capable of being used as an objective key for the classification of organisms, and of proteins. It is also believed that they can be useful in increasing the accuracy of the prediction of protein folding.

Origins of the first cell. A new model for the spontaneous formation of the first living cell based on a novel approach.

Abstract Whether proteins or nucleic acids were responsible for the emergence of life has been debated for a long time. Taking the observation that families of proteins display a remarkable invariance of their amino acid sequence around critical regions, such as active/binding sites, even though these proteins may represent considerable evolutionary diversity, as the naturally provided evidence of evolutionary selection of a working system, the idea is developed that: 1. Proteins had to have been first informational macromolecules that were necessary and sufficient to lead to the emergence of life; 2. it is impossible for a nucleic acid molecules to have formed, by chance, whose base sequence could yield a biologically active protein. A model is proposed to account for the emergence of the first sucessful cell according to this approach.

Probable mechanism of enzyme evolution: How did Ebg of E. coli originate?

A mechanism is proposed for the formation of Ebg-evolved beta galactosidase-of E. coli based on the following assumptions: 1. In the presence of lactose, certain proteins being translated bind to their m-RNA-ribosome complexes; 2. This binding interferes with the release of m-RNA from the bacterial chromosome, marking the gene; 3. Thereupon a cytosine specific methylase and methyl cytosine deaminase pair, modify - mutate - the marked gene; 4. The result, after five or so mutations, is a new gene capable of coding for a different protein which can split lactose; 5. I propose that this enzyme pair has evolved to produce mutations internally, when need arises, as is the case here; 6. This may be a general mechanism through which drug resistance and detoxification of a novel chemical, could be achieved in bacteria; 7. All of these ideas are experimentally testable.

Development of a novel classificatory method — Use of amino acid nearest neighbors as an objective key

Abstract The distribution of overlapping dipeptides found within the amino acid sequence of a protein is biassed, i.e. some dipeptides occur exclusively within angiosperms, some within vertebrates etc., while others are absent from the same organisms. Thus, utilization of the amino acid sequences of the members of a family of homologous proteins, such as cytochromes c, may lead to an objective classificatory system.

Attempts at simulating evolution by a computer: I. Evolution of proteins under prebiotic conditions

The effect of random mutations of five identical pentapeptides that have been inserted arbitrarily along a 100 amino acid-long protein chain has been studied by computer simulation. The method used was the application of mutation probability matrix for 2 PAMs of Dayhoff (1972) repeatedly to obtain the desired length of time. The results indicated that, given sufficient length of time, even the identical peptides could become drastically altered and in order to recognise them as stemming from the same origin one has to use reasonable statistical significance thresholds.

Evolution of the Transfer RNA Molecule Evolution of the Transfer RNA Molecule

Abstract Base sequences of many transfer RNA (tRNA) species obtained from different sources contain homologous regions. These homologies, which are 6 to 20 nucleotides long, occur both within the same tRNA molecule and between many different tRNA molecules repeatedly. Since it is very unlikely an 80 or so nucleotide long tRNA molecule could have been formed at once, under primordial conditions, we propose that the homologous oligonucleotides found within the tRNA molecules to-day represent the earliest adapter from which tRNA molecules have evolved.

Potential of the amino acid homology studies: Homologies found between β-galactosidase and lac repressor of E. Coli

Significant amino acid homologies were found between beta-galactosidase fragments and lac repressor of E. coli using a sliding match according to Greller and Erhan (1974). Since both of these proteins can recognise and bind galactose moiety, we propose that the homologous regions represetn galactose binding site(s) on both proteins. Possible application of homology studies to problems of protein and nucleic acid chemistry is also discussed.

Is there a protein ligase

Results obtained from experiments dealing with mammalian, bacterial, phage and mitochondrial protein biosynthesis as well as certain enzymatically performed amino acid replacement studies on Kunitz trypsin inhibitor strongly suggest that protein ligation may be occuring in vivo. Amino acid substitution experiments prove the reversibility of endopeptidase reactions, and protein ligation is the reverse of endopeptidase reaction. These experiments are discussed in detail and the suggestion is made that ligation may also be useful in the repair of certain essential proteins which may become damaged.

Information density, cellular immunity and transfer factor

Abstract The problem of enzymatic and immunological specificity is considered as a question of recognition of 3-dimensional structure from the standpoint of information content and information density of a molecule. The implication of this model for chemical evolution is given. The idea that a double stranded RNA molecule cannot function as transfer factor (TF) is developed and a model for the formation of TF is suggested.

General theory on the control of cell cycle

Abstract A. Cell cycle control in normal cells: The theory developed is based on the premise of the antagonistic effects of replication trigger (RT) and mitotic inhibitor (MI), both of which are, in all likelihood, glyco-proteins. The former can act either on the chromosomes or on the membrane receptors while the latter acts only on receptors found inside the cellular membranes. The model proposes that: a. These membrane receptors are glycoproteins; b. RT receptors have molecular symmetry and can bind each other and they can move freely within the membranes; c. Primary control of proliferation is due to contact inhibition of movement, whereby RT receptors bind each other and prevent RT from binding them; d. MI acts as a fine control element and particularly during regeneration of tissues; e. Both RT and MI act through cyclic nucleotides. B. Differentiation and aging: This is an extension of the model and further suggests that: a. Differentiation is a result of the asymmetry found in all cells; b. Differentiation is triggered by a decrease of a maternal macro-molecule — a particular mRNA — below a threshold level; c. The initial event is the induction of histone methylases and this event is stimulated by cAMP; d. Aging is an inevitable consequence of differentiation and is due to secondary interactions developing between histones and non-histone chromosomal proteins (crosslinking, ionic-, -S-S- bonds etc.) of the genes that are not needed for daily activities of the cells. C. Neoplastic changes: The flawless formation of these receptors in sufficient quantity, becomes critically important against unscheduled DNA replication and subsequent cell division. Hence any agent — physical or chemical — that interferes with the formation of these glyco-protein receptor molecules as well as that leads to the destruction of the already existing membranes or membrane receptors is a potential carcinogen.