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The game of chess is not a good analogy for protein sequences
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The game of chess is not a good analogy for protein sequences n the May issue of TIBTECH, Ireach W. Mandecki described a path to functional proteins that was 1
analogous to the game of chess. However, a comparison of the game of chess with the computational creation of proteins does not provide strong enough grounds to resolve theoretical questions about functional proteins. In nature, amino acids are not combined to produce proteins; the sequence of the protein is encoded by nucleic acids. The spontanous synthesis of proteins has no chemical basis, as the sequence is not chemically determined. Mandecki acknowledges the difficulties of applying computational combination to protein synthesis by analogy with the game of chess. Functional proteins must be chosen from an astronomical number of possible ones (20100). There is also no computer program presently available that can determine the function of a protein on the basis of its sequence. It seems that, for this reason, human efforts at such a synthesis are fated to fail, except in cases that make use of analogies with known proteins. The author also reached this conclusion, writing that a complete and exhaustive search for the fittest of all possible proteins, a perfect protein, is equivalent to the search for a perfect chess game, and similarly unachievable, both for the scientist working in the lab and for nature. The difficulties of producing functional proteins are found on
several levels – the choice of amino acid, the defined sequence, the desired three-dimensional structure and the problems of multifunctional proteins. It is very important to realize that the computational approach to protein synthesis depends on the supposition that choice of amino acid is free. Mandecki believes that the choice of amino acid in proteins is free, using the phrase ‘amino acids chosen at random’. Strictly speaking, however, the sequence of amino acids is not free in the proteins of living organisms; the sequences of these proteins are defined by nucleic acids in the process of translation. Molecules of DNA create the molecular plan for a functional protein. It is worth considering how far the structure of a protein is planned and what the basis of this plan is. The mol-
ecules of DNA contain a program for the great game of synthesis, the result of which is a living organism. When the author maintains that the structure of a protein of 100 amino acids and 700 nonhydrogen atoms in three dimensions is much more complex than the positions on a chess board with no more than 32 pieces on 64 squares in two dimensions, we must ask the question, ‘Who could create this great plan, which has created tens of thousands of diverse, complicated proteins, billions of cells and many billions of diverse molecules?’ I find more power, depth and wisdom in the molecular plan than in starry skies and the depths of the sea. The conduct of searchers looking for the rules of protein structure in the elements that make them up reminds one of the game blind-man’s buff.
Reference 1 Mandecki, W. (1998) Trends Biotechnol. 16, 200–202
Stanislaw Wronski Institute of Molecular Biology, Jagiell University, Al. Mickiewicza 3, 31-120 Krakow, Poland. (E-mail: [email protected])
Response Dr Wronski’s appreciation Inovoshare for the difficult problems of de protein design and functional prediction from protein sequence. However, I am less pessimistic. Combining computer-assisted protein design with protein-display and -selection methods does offer a plausible path to the discovery of novel proteins; perhaps not ‘perfect’
Letter
Reply
proteins but, nevertheless, proteins having desirable properties comparable with those of natural proteins. Wlodek Mandecki Department of Molecular Immunology, DGI BioTechnologies, 40 Talmadge Road, Edison, NJ 08818-0424, USA. (E-mail: [email protected])
Letters to the Editor Trends in Biotechnology welcomes letters to the Editor that address issues raised in recent TIBTECH articles, or issues related to current developments in biotechnology that are of broad interest to the biotechnology community. Letters should normally be supported by reference to published work. Please address letters to: Dr Meran Owen (Editor) Trends in Biotechnology, Elsevier Trends Journals, 68 Hills Road, Cambridge, UK CB2 1LA. Please mark clearly whether or not the letter is intended for publication.
TIBTECH OCTOBER 1998 (VOL 16)
Copyright © 1998, Elsevier Science Ltd. All rights reserved. 0167 – 7799/98/$19.00
407
The game of chess is not a good analogy for protein sequences n the May issue of TIBTECH, Ireach W. Mandecki described a path to functional proteins that was 1
analogous to the game of chess. However, a comparison of the game of chess with the computational creation of proteins does not provide strong enough grounds to resolve theoretical questions about functional proteins. In nature, amino acids are not combined to produce proteins; the sequence of the protein is encoded by nucleic acids. The spontanous synthesis of proteins has no chemical basis, as the sequence is not chemically determined. Mandecki acknowledges the difficulties of applying computational combination to protein synthesis by analogy with the game of chess. Functional proteins must be chosen from an astronomical number of possible ones (20100). There is also no computer program presently available that can determine the function of a protein on the basis of its sequence. It seems that, for this reason, human efforts at such a synthesis are fated to fail, except in cases that make use of analogies with known proteins. The author also reached this conclusion, writing that a complete and exhaustive search for the fittest of all possible proteins, a perfect protein, is equivalent to the search for a perfect chess game, and similarly unachievable, both for the scientist working in the lab and for nature. The difficulties of producing functional proteins are found on
several levels – the choice of amino acid, the defined sequence, the desired three-dimensional structure and the problems of multifunctional proteins. It is very important to realize that the computational approach to protein synthesis depends on the supposition that choice of amino acid is free. Mandecki believes that the choice of amino acid in proteins is free, using the phrase ‘amino acids chosen at random’. Strictly speaking, however, the sequence of amino acids is not free in the proteins of living organisms; the sequences of these proteins are defined by nucleic acids in the process of translation. Molecules of DNA create the molecular plan for a functional protein. It is worth considering how far the structure of a protein is planned and what the basis of this plan is. The mol-
ecules of DNA contain a program for the great game of synthesis, the result of which is a living organism. When the author maintains that the structure of a protein of 100 amino acids and 700 nonhydrogen atoms in three dimensions is much more complex than the positions on a chess board with no more than 32 pieces on 64 squares in two dimensions, we must ask the question, ‘Who could create this great plan, which has created tens of thousands of diverse, complicated proteins, billions of cells and many billions of diverse molecules?’ I find more power, depth and wisdom in the molecular plan than in starry skies and the depths of the sea. The conduct of searchers looking for the rules of protein structure in the elements that make them up reminds one of the game blind-man’s buff.
Reference 1 Mandecki, W. (1998) Trends Biotechnol. 16, 200–202
Stanislaw Wronski Institute of Molecular Biology, Jagiell University, Al. Mickiewicza 3, 31-120 Krakow, Poland. (E-mail: [email protected])
Response Dr Wronski’s appreciation Inovoshare for the difficult problems of de protein design and functional prediction from protein sequence. However, I am less pessimistic. Combining computer-assisted protein design with protein-display and -selection methods does offer a plausible path to the discovery of novel proteins; perhaps not ‘perfect’
Letter
Reply
proteins but, nevertheless, proteins having desirable properties comparable with those of natural proteins. Wlodek Mandecki Department of Molecular Immunology, DGI BioTechnologies, 40 Talmadge Road, Edison, NJ 08818-0424, USA. (E-mail: [email protected])
Letters to the Editor Trends in Biotechnology welcomes letters to the Editor that address issues raised in recent TIBTECH articles, or issues related to current developments in biotechnology that are of broad interest to the biotechnology community. Letters should normally be supported by reference to published work. Please address letters to: Dr Meran Owen (Editor) Trends in Biotechnology, Elsevier Trends Journals, 68 Hills Road, Cambridge, UK CB2 1LA. Please mark clearly whether or not the letter is intended for publication.
TIBTECH OCTOBER 1998 (VOL 16)
Copyright © 1998, Elsevier Science Ltd. All rights reserved. 0167 – 7799/98/$19.00
407