Spiral Molecular Structures the Basis of Life. mvi ^, ^xmt iU 6 7 7. o/ ^ K SPIRAL MOLECULAR STRUCTURES THE BACIS or LIFE. (Second Edition) - -D - r=\ oy C^.rl F. Krafft, Washington., D. C. s— 3 ■ (-i 1928 1. SPIRAL MOLECULAR STRUCTURES THE BASIS OE LIFE. Introduction. Thoro arc certain iDiological proc3GSGS such as growth, va,riation, and reproduction, which are exhibited by 3V :ry living organism, regardless of its rank in the plant or animal kingdom. These processes establish in nature a sharp line of demarcation between living and ncn-living things, since none of the phenomena of physics or chemistry exhibit anything that is similar or analogous to these fundamental life processes. Biological grov;th involves not only the accretion of tissue-building material, but also many remarkable chemical transformations which take place during metabolism, as well as the dev elopmierit, in m.ost cases, of highly complex and heterogeneous structures. The nearest approach to this in the inorganic world is the growth of crystals, but crystal growth produces neither the remarkable chemical transformations nor the complex structures which often result from biological growth, not to mention several minor differences such as the polyhedral form of crystals as distinguished from the rounded form of most living organisms, and the hardness of crystals as distinguished from the softness of most living tissues. The differences betv^een crystal growth and biological growth are so manifest that it seems hardly fair to assign them to the sam.e category, and much less to pro- pose the one as an explanation for the other. 2S904 2. Biological variation differs from all inor- ganic changes and motamorphosos in that the newly acquired structuroc cxort a directing influence upon the future grov/th of the individual, and are perpetuated "by a process of heredity. Biological reproduction is like-zrisG so dis- similar from any of the other processes of nature that it seems impossible to establish even the remotest analogy, and much loss to attempt to explain it on the basis of any of the known phe- nomena of physics' or chemistry. These fundamental life processes are exhibited just as fully and completely by the simplest bacteria as by the highest plants and animals* All living organism.s, notv;ithstanding their diversity of form and appearance, must possess something in common which gives rise to that peculiar characteristic called "life". If th 3 fundamental life processes are due primarily to some specific configuration of tissues or membranes, then such configuration would have to occur in every living organism, including the simplest bacteria. Y/e find in nature many structural uniformities which occur more or less extensively among certain species of plants and animals, but these are the result of evolution and v;ill be found to disappear as we go down the scale of plant or animal life. Even the chromosomes which occur in the cells of all higher plants and animals have never ^03on observed in any of the bacteria, and therefore cannot be regarded as th-e primary and original cause of the fundament^-! life processes. It would not be justifiable, in the absence of experimental proof, to assume that chromosomes or similar structural complexities exist in bacteria, merely because they have been observed to exist in the cells of the higher plants and animal s . 3. That the fundamental life procossss must "be duo, either wholly or partly, to specific chemical structures is generally admitted, hut there is a pr availing opinion that the molecular structures which are necessary for this purpose must be extremiCly complex. The failure of all previous efforts to devise some type of molecular structure which would function in a manner similar to the fundamental life processes does not, hov/ever, prove that the solution of the problem must lie in the direction of extreme complexity. The complex molecular structures of which the higher plants and animals are comiposed have developed gradually in the course of evolution, and the fact that they are necessary for the proper physiological functioning of the particular organisms in vjhich they now occur.;- does not prove that they v^ere also the original cause of the fundamental life processes in the more primitive ^'xrganisms from v/hich these higher plants and animals have developed. If extremely com^plex molecular structur3S v-^ere necessary for life of any sort, then it vfould he highly im- prchabl e that life could ev 3r have originated spontaneously. 4. The Ch3mic^l Basis of Life. If life cannot bo due, prirr.arily, either to specific arrangaments of tissues or inemToranes or to extrernely complex molecular structures, then it must be due to some comparatively simple principle of chemistry vrhich has not yet been discovered. To find a cluo to this we must in- vestigate the molecular structure of prot3ins, because those constitute practically all the structural material in the bodies of the simplest unicellular organismiS after removal of the vat 3r, Althougl': small amounts of fats ar ^ also present, yet these do not constitute structural material but appear to be merely the by-products of certain kinds of protein metabolism. Protein substances, upon hydrolytic decom- position, always yield a mixture of amino acids or their dik etopip erazine derivatives. To the alpha carbon atom of these acids thsra is alv/ays attached one amino group and one hydrogen atom, and usually also a more complex group, so that they may be represented generally as foilov/s: ITH2-CKR-CO-OH. The structural formulae of the more im- portant ar;:ino acids are as follows: 5. Glycine COOH t HCH » Alanine Serine ITHo Cystine HGOC t HgN Aspartic acid COOK CK3- -CH f KKg COOH t HOCH2— - CH 1 ITH2 COOH T .0 -S-S-II oC — CH ^ 1 1^2 COOH 'OC-CH2- -CH KH2 Proline CGCH CH^ » '2 ^- HgC CH- Oxyprol ina HOCK 6. CH. CH. COOK f CH » Glycine-prolin 3 anhydride (E. A"b4erhald*n & 15. Komrn, Z. physiol. Ch-TH., 145, 308, 19.^5.) Hp,Q K^C / CO — CH / TJ \ CH — CH. ^ UK / CO Glutamic acid HOOC-CHg-CHg- COOK ! ■CH t ITK^ Ornithine COOK f NHg-CK^-CHg-CHg— CH rlH o 7. Histidino CCOH / C-CKo — CH hi: I " » CH "^ "^ Arginins ITH Caprins CO OH f CH3-CK2-CH2-CH2— CH ITHo Lysin3 CCOH ! H2N-CH2-CH2-CK2-CH2 — CH ^2 Valina COOK f " CH—CK CH3 . CH3 \ jMHo COOK >TH^^ » C-m--CH2-CH2-CH2--CH L 3Ucin3 8. COOH CH. CH. CH-CKo — 2 CK t Iso-] 2ucin3 CCOK CK ^-. CH- CHs-CK^'- OH T.TTT Ph anyl - al r.,nin 9 H HC - C C C '^' H .C-CKg- COCK f CH f Tyrosma H HOC C '■■ C - H H 'I *^ C H C— Uj.Xo' COOH ■CH » 9. Tryptophp.n 3 H COOK - C :.,^ ' HC ^ '^- Q- -• C~CHp — OK ii i if "^ HC /-C . CH H i]H t Leucin3-gluta,!i]ic «.cid .anhydrida (p. A. L?vin3 & W.A. Beatty, Ber. 59, 2060, 1906.) ^, CO — ITIi^ ^ CK3 HOOC-CHp-CK^-CH'" ^Z. CH-CHp-CH ^ ^ ^ -^ i:tT CO -^ ^ -^ CH3 Valyiz-leucine (?:. Abderlial den, Z. Physiol. Oh 3m., 131, 284, 1923.) CH^ .CO — :iH .^ ^. CH3 ^^ CH- CK : '^ CH- CHg - CH '" CH3 "" ""■mi — CO -^'^ ^^^^ CH3 Leucine anh^.^dride (E. Aoderhalden & K Punk, Z. physioi. Che-T,. 53, 19, 1917.) CH^ CO — KH^ ,,.CH3 '"'^ CH- CHp - CH '^' ^ CH- CHo - CH " CH^-^' ^ irn — CO "" ^ "^"CiHj 10. Th3S3 amino acids will readily cond-Dnsc, v/ith the 3liTnination of water, to form eithsr chain structurss known as polypeptides, or ring structures knovn as dik etopiperazines . (Smil Fischer, Unt 3rsuchung 3n liber Aminos^iuren, Polypeptide, und ProteSne, 1899 - 1906; Plimr::er's Chemical Constitution of the Proteins, Monographs on Biochemistry, Longmans, 1912) 3 NHg-CRK-CO-OH = im2-CRH-C0-!'^-CRK-C0-lTK-CRPI- CO-OH + 2 HO; 2 NHg-CRH-CO-CK = CRH CO,,^ HN ■ ^^IIH + 2 H9O "^•CO • CRH--^'' ^ Since protains constitute the principal structure-lDuilding food for animals, and upon digestion are decomposed into amino acids, in v^hich form th 3y are assimilated by th 3 tissues, it is gensrally thought that the phenomenon of grovjth involv 3S condensation processes of a similar character. The frequent occurrence of diketopiper- azine rings among th 3 disintegration products of proteins seems to indicate that this may be the form in which the alpha am.ino acid groups occur in nature, but a fatal objection to this thsory is that diketopiperazines cannot grow by con- densation with additional amino acid molecules. If our purpose is to solve th 3 problem of life, then the biological side of the probl 3m must be given full consideration, and we should have but little patience with any theory which explains only the chemical but not the biological facts. II. The polypeptide thoory teaches that the amino acid groups occur in nature in the form of long polypeptide chains. This theory offers at least a partial explanation for the phenomenon of growth, as well as for structural variation, hut in its present form is inadequat3 in th^\t it does not account for that definite morphology which is possessed "by all living organisvns, nor for spontaneous division with the transmission of hereditary charact sristics to the progeny. There is, however, another type of struc ture, namely the helical spiral, which retains the 3ssential characteristics of both the ring and the chain. 12. Polypoptids S-pJrals. If W'3 as sum 2 that th 3 val?nci3S of the carbon ato^ ar3 arrang3d like th s corners of a regular tetrahadroE, and that th 2 three val3nci9S of tri-val ent nitrogen in amino compounds are about 3qual]y distributed around an equatorial circle, (vhich arrangement appears to b :- the only on ^' that is consistent with rill knov/n chemical facts,) then the polypeptide^ chain may be coiled around on itself so as to form a "• h el i c al sp i r al h av i ng sub s t an t i al 1 y th 3 s am 3 di^jT:]eter as the diketopip erasine ring. KO ^ / L J C7/ H-N 0 \ C HO '/ n / \ R H / \ R K A polypeptide spiral in KaCl solu 1 33. Th D nitrog?n atoms v.'ill appear in tv/o rovs on opposit3 si^.3s of th3 ppiral , and the co^npl 3X tid3 chain? r3pr3S3ntod by th s R's in th ? previous equations, as well as th 3 carbonyl gr-oups, wil] 1 i.k 'Wis 3 arrang3 th3Tnselv3S along other diaTri3tri- cally opposite lines. Chsrr.ic^J. union will probably tak3 place b3tw3en th 3 succes?iv3 nitrogen atoviis by virtue of th3ir fourth and fifth valenci3S, and p3rhn.ps also betv^een th 3 successive carbonyl groups in the manner sho^.vn. The nitrog3n atoms at th 3 3nds of the spiral will probably units with th 3 ions of inorganic salts, th 3 pr3Senc3 of which is n3C3ssary for th3 nourishmsnt of all living organisms. It will b? found upon actually con- structing this spiral of atomic models that thECs is •■^mpl ? room for th3 complex sid3 chains R if the fourth valency of th 3 alpha carbon atom is occupi3d by hydrog3n, but that th 3 pr3sence of rnoT 2 complex groups in this position would make the spira] structur3 impossible. We find, hov;e-B3r, that the decom.position products of proteins always have a hydrogen atom in this position. It will be observed that the polyp 3ptide spiral in the accompanying diagram has an 3xposed amino group at one end, and an exposed carbonyl group at the other end. Th eor 3ticall y it appears that additional amino acid radicals could be add 3d to eithsr end of th 3 spiral, although there may be some at pr3sent unknown reason why growth can take place at on 2 end only. A spiral with an expos ?d amino group at th j free end may be d3sig- nated as positiv3 { + ), and on3 with an 3xposed carbonyl group at the fr3G end as negative (-). A distinction should also b j made betw3en right- hand 3d (r) and left-handed (l) spirals. 14. Th 3 similarity in forTj and app 3aranc : of a polypeptide spiral to a "bacillus or a spirillum will be apparent. It should be capable of graving -endwise by condensation with additional amino acid radicals, and as long as tho spiral form is main- tained the structure will possess definite mor- phology. It must remain permanently right-handed or left-handed which appears to account for the optical activity always s^±Libited by substances obtained from living organisms. It should be capable, during growth, of acquiring different arrays of side chains upon being nourished with different kinds of amino acids, and thus exhibit the characteristic of variability. It would not, however, upon division, be capable of transmitting to its progeny any permanently inheritable ch ' rac teristics, and can therefore not be regarded as a complete living organism. 15. The Linking of Pol ypeptide Spirals Since th ^ distance between the centers of adjacent carbon atoms is about 1.54 x 10"® cr. , the diameter of a pol;>'p ept ide spiral, as measured between the centers of the •^toms, would be ^bout ?.l X 10~° cm. It will therefore require several hundred spirals arranged side by side to produce an organism^ at large ^s the sm.a]lest visible bacillus, whijQh m2asure3 about 1000 x 10"^ cm in diameter. In order that the organism may possess definite individual characteristics, these spir'-Qs would hav b to be coupled together in some permanent m.anner, but after they are thus coupled tog 3th er, they will have a tendency to preserve their arrangs-ment throughout growth, and if trans- verse fission occurs, each portion would hav3 to continue growing according to the originpJ pattern, There will thus be exhibit 3d, in the simplest possible mann3r, a proc3ss of inheritanc3 by vmich parental characteristics are preserved throughout growth and transmitted to th 3 progeny. It appears that there ar 3 only a limited numbsr of ways in which adjacent spirals can be connect 3d tog3th3r. The connecting ccm.plexes must be conparat iv 3I y simple, b?caus 3 if more than a cert^^in number of int srmiDdiat 3 atoms are pr3S3nt their m.ovBmonts v:ill no longer be definit3ly coordinated so as to form th 3 r required int3rmediat3 structures, but will b3 m5r3 or 1 3ss at random. In ord3r to d?t3rmin3 the nature of thes3 conn3cting complexes, th 3 use of atomic models is r 3ccm.mend 3d, b'^caus3 the probl 3ms encountered hsre ar 3 structural rather than dynam.ic . Th3 form of most fraquontly in conn Oct ion lD3twien of a C3ntra] ^^arbo which aro usua]ly atoms of amino aci from such connscti a study of protein two typ^s of such pro t 3 ins . 16. connecting complex which occurs natur3 appears to be a triple thrcD adjacant spirals by m, 3-^ns n atom. The compl 3X groups attach 3d to the alpha carbon ds arc 3vid3ntly the fragments ng comp] exes. It appears from d 3composit ion products that tripl 3 connections occur in Leucine, phenyl -al an in e, and tyrosine have a triple junction at th 3 gamma carbon atom, with an intermediate -CHo- group between this triple junction and the -CH IHig-COOH group. The complete tripl 3 junction, (assuming it to be the same on all thr3e sides,) tog 3th er with one-half of each of the three adjacent spirals, will therefore app ear s omi ewh at as follows: OC MI \ \ CH CH^ CH CH, CK, 1^: — CH CH CO CO HF A triple junction of the gamima-gamma-garrima type. 17. which liii r P^°^-:^^y ^'-^- typ. of trip! 3 junction whichwill form most rs-'^.dily in naturo. b^causo if thev wn,nT>;^'^'; "'''2- groups W3re introducad they would have too much f r -dom of mov 3m 3nt to produce the triple junction spontaneously. Hydro- carbon chains will not react with 3ach oth^r ^f they are capable of movement at random in any^ wnnTr^""'''.^''? ^^^^ '" ^^^^ ^^' condition which would exist at any point biyond th3 gamma carbon -^A. "^^* 2" "^^^ 0th 3r hand, we omit some of th - xntarmediate-GHg-^- groups and attempt to form the triple junc-:ion at the b3ta carbon atom th - spirals will have to b3 brought so cl.os3 togeth-r that there would probably be considerable repul- sion betwaen them due to th 3rmal vibration of th - atoms. Such a triple junction could prooably not form spontaneously unl 3ss the spirals were crowded together from the outsida, but the prssence of substances like iso-leucins and valine ^Tiong th - decomposition products of proteins seems to show tnat triple junctions of the beta tyiDe do occur at times. The existence of both beta and g=^mma junc- tions in the same prot 3in is indicated by the occurrence among protein decomposition products of^ substar.ces like val yl -1 eucin 3 which contains a beta junction at one end nf the rnol ecul 3 and a g^mma junction at the other end. If W3 connect togeth3r a lar/^3 numb 3r of spirals by means of triple junctions of eith sr the beta or ths gamma type, th ay will form coll ectiv sly a cluster of hexagonal compartments. 18 The cellular structure of proteins. In living tissues these will "be filled with water or dilute salt solution, and it will be observed that the vacant spaces in these compartments have a combined cross-s ection