A Newly Discovered Stereochemical Logic in the Structure of DNA Suggests That the Genetic Code Is Inevitable

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A NEWLY DISCOVERED STEREOCHEMICAL LOGIC IN THE STRUCTURE OF DNA SUGGESTS THAT THE GENETIC CODE IS INEVITABLE LAWRENCE B. HENDRY* EDWIN D. BRANSOME, JR.* MARION S. HUTSONJ and ULUAN K. CAMPBEUt Thirty years ago Watson and Crick described the structure of the B form of deoxyribonucleic acid (DNA) and accurately predicted that the complementarity ofpaired bases in the double helix provided "a possible copying mechanism for genetic material" [I]. The discovery (initially described in thisjournal [2]) of a variety of complementary stereochemical relationships between DNA and diverse biologically active small molecules (steroid hormones, phytohormones, neurotransmitters, pheromones , vitamins, mutagens, etc.) [3-10] implied that there were additional features of fundamental biological importance inherent in the structure of DNA. Namely, the precise structural specifications for the chirality and framework of molecules involved in cellular function appeared to be reflected in the physicochemical properties and unique configuration ofDNA. Our extension ofthe principle ofcomplementarity beyond base pairing to other aspects of the double helix suggested that there was a fundamental, logical stereochemistry embodied in gene structure. We have decided to term this discovery the "stereochemical logic" of gene structure. The stereochemical logic is defined as those unique features of DNA structure that ultimately dictate constraints on the structure, function, metabolism, and biological activity of small molecules [8]. The authors thank B. B. Webber, T. Muldoon, V. B. Mahesh, andJ. Tyler for comments and for review of the manuscript; M. Petersheim, F. Witham, O. L. Chapman, T. Feir, W. Hendry, F. Lehner, E. Chargaff, and E. Kline for providing original insights and encouragement ; C. Natoli, J. Craig, W. Stenstrom, and K. J. Hendry for valuable technical assistance; R. Feldmann for providing space-filling X-ray coordinates and fig. 6. ?Departments of Medicine and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912. !Department of Pathology, Medical College of Georgia, Augusta, Georgia 30912. ^Department of Medical Illustration, Scottish Rite Hospital, Adanta, Georgia 30363.© 1984 by The University of Chicago. All rights reserved. 0031-5982/84/2704-0399101.00 Perspectives in Biology and Medicine, 27, 4 · Summer 1984 | 623 TABLE 1 The Genetic Code* Second Base 5' First Base T(U) 3' Third Base T(U) Phe Phe Leu Leu Leu Leu Leu Leu He He lie Meet Val Val Val Val Ser Ser Ser Ser Pro Pro Pro Pro Thr Thr Thr Thr Ala Ala Ala Ala Tyr Tyr Stop Stop His His Gin Gin Asn Asn Lys Lys Asp Asp Glu Glu Cys Cys Stopt Trp Arg Arg Arg Arg Ser Ser Arg Arg GIy GIy GIy GIy T(U) C A G T(U) C A G T(U) C A G T(U) C A G •Adapted from [40]. tTGA can code for trytophan. tStart codon for protein synthesis. In this paper, we provide the first comprehensive description of how the stereochemical logic derived from complementary aspects of DNA structure is manifested in both the triplet nucleotide sequences of the genetic code and in the structures of the select group of 20 amino acids involved in protein synthesis. Some of the implications of our findings for understanding the nature of biological coding are also discussed for the first time. Synopsis ofResults We have examined cavities created when a single base is removed from molecular models of the Watson and Crick structure of DNA. We chose to remove a base for several reasons (see Appendix); one was that the bases appeared to be structurally analogous to amino acid side chains and thus could be replaced by amino acids in our molecular models [35 ]. Removal of a base results in only 64 unique cavities; the cavities correlate with the 64 possible triplet codons in the genetic code (table 1). A given cavity is thus a representation of the space created in a codonanticodon , double-stranded, triplet sequence with the second codon base 624 I Lawrence B. Hendry et al. · Stereochemical Logic in DNA removed [3]. Stereochemical relationships between the cavities are remarkably consistent with the pattern of the genetic code; moreover, the 20 common L-amino acids that are coded for during protein synthesis fit stereospecifically into those cavities derived from their codons. Those readers who are interested in the scientific details of our approach , please...