Gopinath Kartha and the Birth of Chemical Crystallography in India

HISTORICAL NOTES

Gopinath Kartha and the birth of chemical crystallography in India

P. Balaram

Gopinath Kartha was an extremely modest showed that while in large-angle scatter- was widely known, for his work on and soft-spoken scientist, whom I met ing the haloes reflected specific mole- the collagen structure with G. N. Rama- only once when he visited the Indian cular sizes and packing shapes, small- chandran at Madras University in 1954– Institute of Science (IISc), Bangalore, in angle scattering was directly related to 1955, and his later structure determina- the early 1980s. His reputation preceded the statistical fluctuation of density in a tion of the enzyme ribonuclease, in him. His name was indelibly linked to liquid. Second, Raman knew that Bragg’s David Harker’s laboratory in Buffalo, the Ramachandran–Kartha triple helical first structure of naphthalene was not New York. In the narrative that follows, model of the fibrous protein collagen consistent with its birefringence, while I try to describe Kartha’s trail of research proposed in the period 1954–1956. This the second one was. With this as cue he and his impact on crystallography, in model, one of the major scientific tri- and his school launched extensive studies India and beyond, through his four mole- umphs of newly independent India, has on the optical and magnetic anisotropy cules, all of them ‘firsts’ in different been celebrated in the decades that have of organic crystals to get vital informa- ways. followed, most notably by the christen- tion on the arrangements of molecules in ing of the large auditorium at the Central the crystalline state. Third, one of his Leather Research Institute (CLRI) in students, Kedareswar Banerjee, was Barium chlorate monohydrate Madras (now Chennai) as the Triple He- amongst the earliest to probe into the lix Auditorium (Figure 1), its name visi- problem of phase determination by direct The three-dimensional structure of ble as one drives along the busy road in methods and for this he used Bragg’s BaClO3 shown in Figure 2, taken from front of the institution. I met him to dis- data on naphthalene. Unfortunately, in Kartha’s Ph.D. thesis3 submitted under cuss our mutual interest in the structures spite of this early lead, it was not until the guidance of Ramachandran, is the of peptides, in the hope that he would be 1951 that the first crystal structure was first molecular structure determined by interested in molecules being produced solved in India using Fourier methods by X-ray diffraction in India. Kartha’s use in my laboratory. He graciously agreed Gopinath Kartha.’ The last two sen- of ‘two dimensional Patterson and Fouri- to study them and shortly after his visit I tences drew my attention. Banerjee was er projections along three axes’ and his mailed promising crystals to his Buffalo, reinterpreting J. M. Robertson’s analysis application of the heavy atom method New York address. Some months later he of Bragg’s data on anthracene and naph- might rightly be considered as the first requested more crystals which we mailed thalene2. The statement that Gopinath stirring of chemical crystallography in rather quickly, hoping that his skill in Kartha solved the first crystal structure India4. In his report, Kartha notes that the structure determination would provide us in India led me to ask myself: What was intensities of the diffraction spots ‘were a view of the molecule. Sadly, he died the molecule and where was it publi- corrected for Lorentz and polarization suddenly, in 1984, even while he was shed? Should not this ‘first’ be celebrated? factors, according to Buerger & Klein engaged with this problem. At that time, From the recesses of my memory, I could (1945) in the case of the c-axis photo- I was unaware of much of Kartha’s work, hazily recall hearing from friends in graph and according to Kartha5 for a- and but realized over the years that he was organic chemistry of another important b-axis photographs’. Seven decades later, undoubtedly one of the pioneers of Kartha structure, morellin, a complex reading these sentences and going back chemical crystallography in India. natural product. Kartha, of course, to look at the original papers, one can My interest in Kartha was further fuelled when I read the following para- graph in an article by Sivaraj Ramase- shan on Dorothy Hodgkin’s Indian connection1: ‘In the twenties, India had developed a fairly strong tradition in X-ray physics. The six-week visit of C. V. Raman to Europe in 1921 greatly changed his research interests. On see- ing the blue of the Mediterranean, he started his researches on the scattering of light in liquids which finally culmi- nated in the discovery of what is now called the Raman Effect. His encounter with Sir William Bragg and his work on naphthalene structure started three lines of research in India. First, Raman fabri- cated an X-ray tube and was amongst the earliest to use X-ray diffraction as a Figure 1. a, The Triple Helix Auditorium at the Central Leather Institute, Chennai. b, A structural tool to study liquids. He model of the Ramachandran–Kartha triple helix of collagen.

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Box 1. Biographical Note Gopinath Kartha (26 January 1927–18 June 1984)

Gopinath Kartha was born in Shertallay (now Cherthala), Alappuzha District in Kerala where he spent his child- hood and had his early education. He studied at the Sanathana Dharma Vidyasala at Alappuzha, passing out in 1942. He was at the Maharaja’s College in Trivandrum (now Thiruvananthapuram) for the Intermediate pro- gramme in 1942–1944. He graduated in 1948, with a B.Sc. (honours) degree in Physics and Mathematics, from Presidency College, Madras. He received an MA degree in Physics from Madras University and an M.Sc. degree from Andhra University, Waltair (Vishakapatnam), both in 1949. In the same year, he joined the Indian Institute of Science (IISc), Bangalore to work towards a Ph.D. degree in the Physics department under the guidance of G. N. Ramachandran. As IISc did not grant degrees then, he was registered at Madras University, and completed his work in 1953. He moved to join Ramachandran in Madras (now Chennai) in 1952. In 1955, he spent a year at the Cavendish Laboratory in Cambridge (UK), before moving to the National Research Council (NRC), Ottawa, Canada. In 1959, he moved to David Harker’s laboratory at the Brooklyn Polytechnic, New York. Later that year he moved with Harker to the Roswell Park Memorial Institute, Buffalo, NY, where he would spend the rest of his career. He held appointments as research professor in the Roswell division of SUNY at Buffalo and as research professor at Niagara University. In 1961 he spent six months as a Reader at Madras University. He was at the University of Kyoto, Japan as National Research Professor in 1972–73.

6). But even as he worked on his thesis, Kartha obtained crystals of a more complex molecule of unknown constitution, morellin, from P. L. Narasimha Rao’s laboratory in the Biochemistry department of IISc.

Morellin

A yellow crystalline pigment, christened morellin, was first isolated in the laboratory of John Simonsen (1884–1957), then Chief Chemist at the Forest Research Institute and College, Dehradun, probably in the 1920s (ref. 7). Simonsen, whose lasting contribution to his field was his monumental five-volume treatise The Terpenes, published between 1931 and 1957, became Professor of Organic Figure 2. a, Title page of the Ph.D. thesis submitted by Gopinath Kartha to Madras Chemistry at IISc in 1925, a position he University in 1953 based on work at IISc, Bangalore. b, Arrangement of atoms in the held until 1929 (ref. 8). It was here that structure of barium chlorate. he suggested that a younger colleague, B. Sanjiva Rao take up the study of this only marvel as to how far the field has student in 2021 consider barium chlorate novel substance isolated from ‘the dry progressed. A cursory glance at the con- an important molecule? Undoubtedly, powdered pericarp of the seeds’, of the tents page of the Acta Crystallographica not. Yet, it is these inorganic substances, evergreen tropical tree, Garcinia morella7. issue in which one of Kartha’s papers containing atoms with high atomic num- In the first report on the characterization appeared5 reveals that he was in good bers (‘heavy atoms’) that dominated the of morellin, by Sanjiva Rao, a molecular company; J. Donohue and K. Trueblood evolution of crystallography in its early formula of C30H34O6 was deduced. The describing the structure of hydroxypro- years. Those readers who are historically short report in the 1 January 1937 issue line, R. Pepinsky and others reporting the inclined might do well to read David of the Journal of the Chemical Society structure of colchicine, R. E. Marsh on Harker’s description of how he came (London) is replete with experimental the structure of diphenyl diselenide and upon the Harker sections, now famous detail, but the author concluded cautiously: W. L. Bragg describing a device for in the lore of crystallography, while ‘…the evidence at present available is calculating structure factors. Bangalore working on the structure of the minerals, insufficient to warrant the assignment of was beginning to make its presence felt Ag3AsS3 and Ag3SbS3, in Linus Paul- any structure to morellin…’. Narasimha in the world of crystallography. Would a ing’s laboratory in the mid-1930s (ref. Rao (1913–2013), who moved from the

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Organic Chemistry department at IISc to graphy, the structure of morellin from pretation is facilitated by the Kartha the Biochemistry department, resumed the available data would have been prac- structure. Kartha had moved to the Ros- work on morellin9 reporting further tically impossible. By 1954, Ramachan- well Park Memorial Institute in Buffalo, chemical work aimed at determining the dran and Kartha had begun their attack New York in 1959 and it is here that he structure in the early 1950s (ref. 10). In on collagen. completed the morellin structure, at a their 1954 paper Rao et al. note: ‘Al- The research on morellin would get time when he was determining the struc- though the elementary analysis of a boost, a few years later, with the entry ture of ribonuclease. The crystallographic (morellin) is in good agreement with the of K. Venkataraman, who developed a section of the 1963 paper on morellin previously assigned formula C30H34O6, major natural products centre at the ends with a promise ‘The absolute confi- X-ray method (unit cell dimensions), National Chemical laboratory (NCL), guration has not yet been determined. a = b = 15.89 ± 0.04; c = 11.60 ± 0.02 A; Poona (Pune), with a focus on pigments. The details of the structure analysis will density of crystals, 1.234 now gives a Morellin’s colour may have undoubtedly be published elsewhere.’ That promise value of 544 ± 10 for its molecular attracted him. Venkataraman was one of was never kept. weight. We like to reserve an explanation India’s foremost organic chemists at that Kartha was not a scientist who pub- for this discrepancy.’10 A footnote in time and the first Indian director of NCL. lished prolifically. He drew his pleasure their paper acknowledges personal com- It is in Pune that a p-bromobenzenesul- from solving problems. Morellin was a munication from Gopinath Kartha, at phonyl ester of morellin was prepared. difficult one. It is to be hoped that this Madras University, for the molecular The presence of the heavy atom bromine resurrection of the history of the struc- weight estimation from unit cell volumes and the moderately heavy atom sulphur ture determination of one of the most of morellin single crystals. Rao also permitted structure determination using complex natural products of Indian ori- noted the relatively unpromising antimi- methods that had foundations in Rama- gin and the first natural product whose crobial properties of morellin. chandran’s theoretical work in crystallo- structure was revealed in India by X-ray In his first attempt at determining the graphy13. The structure of morellin diffraction will challenge a new genera- structure of morellin, Kartha, then a stu- (Figure 3) revealed a complexity14 which tion to revisit morellin and ensure that dent in the Physics department at IISc would have been extraordinarily difficult three dimensional coordinates become determined the unit cell dimensions of to unravel in the 1950s. The correct available. This would be a fitting tribute crystals provided by S. C. L. Verma, an molecular formula for morellin was now to Kartha and his dedicated collabora- associate of Narasimha Rao, who also established as C33H36O7 corresponding to tors. In the era of classical natural determined the crystal density. Based on a molecular weight of 544, in complete product structure determination, best these observations, Kartha noted: ‘…we agreement with Kartha’a initial 1954 exemplified by complex molecules like get the value 544 for the molecular estimate11 of 540 ± 10. In a lecture pre- strychnine, total chemical synthesis and weight. The value measured by chemical sented a decade after the report of the demonstration of the identity of the syn- methods was 483 whereas the suggested morellin structure, Venkataraman pre- thetic and natural substances was the 15 formulae C30H34O6 and C29H32O6 give sents a masterful overview of all the final test. For morellin, this is a symbolic the molecular weight 490 and 476, re- chemical and spectroscopic evidence goal still to be reached, building on many spectively. The X-ray molecular weight accumulated for morellin, whose inter- efforts in this direction16. In reflecting on 544 (which has an accuracy better than ±10) is thus definitely higher’11. The use of cell volumes and crystal density to estimate molecular weight (mass, in today’s usage) of a complex natural product of unknown constitution might have been done for the first time in India, a rare in- cursion of physics into organic chemistry. This was the first sign that chemical methods may have hit a road block on the way to the structure determination of morellin. Kartha’s paper was communi- cated in January 1954 from Madras Uni- versity, with an acknowledgement to Ramachandran, to whose laboratory he had moved from Bangalore. A few months later another very brief commu- nication followed in July 1954 on morellin this time with the IISc, Bangalore address in which limited progress had been made, permitting assignment of the space group, with the promise that ‘de- 12 Figure 3. Views of the morellin constitution: a, Projection of structure determined by tailed analysis is in progress’ . In the era X-ray diffraction14; b, Chemical formula as drawn in ref. 14; c, Three dimensional model before direct methods of phase determi- generated using chemical structure on PubChem; https://pubchem.ncbi.nlm.nih.gov/ nation revolutionized chemical crystallo- compound/Morellin; d, Chemical formula as drawn in ref. 15.

CURRENT SCIENCE, VOL. 121, NO. 3, 10 AUGUST 2021 443 HISTORICAL NOTES the heroic chemical work of Sanjiva Rao, of personal interrelationships occur in lagen from Madras appeared in Novem- Narasimha Rao, Venkataraman and their much if not all scientific work. Consider, ber 1954, in this journal24, which Rama- associates on morellin, it may be worth for example, the discovery of the basic chandran edited from 1950 to 1957. The recalling Robert Robinson’s words in his structure of collagen, the major protein Current Science paper reported the key obituary of John Simonsen8: ‘His scien- of tendons, cartilage, and other tissues. diffraction data which led to the right tific work was throughout of excellent The basic fiber of collagen is made of structure. The authors, Ramachandran calibre and absolutely reliable. He was in three long chains wound around one and his student G. K. Ambady, describe several cases unfortunately misled by another. Its discovery had all the ele- the earlier model as ‘consisting of three unusual rearrangements and he did not ments that surrounded the discovery of cylindrical “ropes” each rope contain- have the advantage which certain modern the double helix. The characters were ing three helical chains’. The imagery of techniques, especially infra-red spectro- just as colourful and diverse. The facts the rope is striking. Many years later I graphy and chromatography, have con- were just as confused and the false solu- heard Ramachandran in a lecture de- ferred on present-day workers in the tions just as misleading. Competition and scribe the moment that the coiled helix difficult fields that he sought to culti- friendliness also played a part in the story. model struck him, as he watched his wife vate.’ Yet nobody has written even one book plait her hair in the traditional South about the race for the triple helix. This is Indian manner. I was reminded of the surely because, in a very real sense, col- rope analogy when, in collecting material Collagen lagen is not as important a molecule as for this article, I corresponded with one DNA. Of course, this depends to some of Kartha’s associates, K. I. Varughese. The collagen structure is an important extent on what you consider important. He wrote: ‘In 2007, during the meeting landmark in our understanding of the ste- Before Alex Rich and I worked (quite by (honoring Dr. Kartha) at Vaikam, Kerala, reochemistry of proteins. Ramachandran accident, incidentally) on collagen, we I heard for the first time about a possible and Kartha published their triple helical tended to be rather patronizing about it. source of inspiration for the discovery of model17,18 in 1954–1955, close on the “After all,” we said, “there’s no colla- the triple helix. Earlier, the Alappuzha heels of Pauling’s single chain alpha- gen in plants.” In 1955, after we got area where Dr. Kartha grew up was the helix (1951)19 and the iconic Watson– interested in the molecule, we found center of the coir industry. A three Crick double helix in 1953 (ref. 20). In ourselves saying, “Do you realize that stranded coir rope is like a coiled triple many ways the collagen structure (Figure one-third of all the protein in your helix. I must add that Kartha had never 1) may have been intuitively the most body is collagen?” But however you mentioned this to me.’ The 1954 Current difficult, unconstrained as it was by mul- look at it, DNA is more important Science paper was quickly followed in tiple intra-chain hydrogen bonds, a con- than collagen, more central to biology, September 1955 by the Ramachandran– sequence of the abundance and regular and more significant for further re- Kartha paper in Nature which presents a repetition of the imino acids proline and search. So, as I have said before: it is more detailed and revised model of the hydroxyproline in its sequence. This was the molecule that has the glamour, not triple helix, essentially the structure that the era of X-ray fibre crystallography, a the scientists.’ has stood the tests of time18. Controversy technique which yields limited diffrac- Ramachandran moved to Madras Uni- soon followed as criticisms of this struc- tion intensity data, diagnostic of the reg- versity in September 1952, as the head of ture were levelled, most notably by Rich ular arrangements of the constituent unit the newly formed Physics department at and Crick. An unexpected fallout of this along the repetitive polymer chains con- the young age of 30. Gopinath Kartha, turbulence of the mid-1950s, was that it stituting the fibre. The key to structure his student in Bangalore moved shortly spurred Ramachandran to embark on his determination is to build stereochemically thereafter now in the role of a post- now famous analysis of polypeptide con- acceptable models which can then pro- doctoral fellow. Years later Ramachan- formations, resulting in the map that now vide a fit to the observed data, using the dran would tell his biographer that bears his name, immortalizing him in the then known geometries for the monomeric Kartha was the best ‘post-doc’ he ever literature of biochemistry and structural constituent units of the biopolymer had. The collagen story in its entirety as biology. Some of the key insights into chain. For the alpha helix, Pauling had seen from Madras is narrated with many the discomfort that the Madras collagen used two crucial pieces of structural insights in the Ramachandran biography triple helix, caused in Cambridge (F. H. information in constraining his model by Raghupathy Sarma22, who draws on C. Crick) and London (J. T. Randall) building; the planarity of the peptide unit Richard Dickerson’s classic overview of come from letters that Kartha penned to and the formation of intrachain hydrogen the field of protein structures as seen in Ramachandran from the Cavendish labo- bonds between the donor NH groups and the 1960s (ref. 23). The first paper ratory (Figure 4). Collagen had placed the acceptor carbonyl groups repetitively describing the three-chain structure Ramachandran and Kartha in competi- present along the polypeptide backbone. appeared in Nature in August 1954 (ref. tion with the most famous names in the The Watson–Crick story is too well 17). The unit cell dimensions are repor- field, Pauling, Crick and Randall, names known to bear retelling. The Chargaff ted and a nine amino acid model is con- which readers may recognize as charac- Rules provide a dramatic constraint on structed to fit the dimensions. This report ters vividly portrayed in James Watson’s, possible models, now immortalized as reinterprets fibre diffraction data in the controversial, but now classic, book The Watson–Crick base pairs. Fresh from literature, differently from published Double Helix. In one of the finest chap- their triumphs, both Pauling and Crick interpretations by W. T. Astbury, Linus ters of science in post-independence turned to collagen. In Cricks words21: Pauling and R. B. Corey and R. S. Bear. India, the Madras laboratory pipped ‘Misleading data, false ideas, problems The first fibre diffraction pattern of col- Cambridge and Caltech to the post.

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Figure 4. Letter from Gopinath Kartha (Cambridge) to G. N. Ramachandran (Madras) dated 4 December 1955.

Gopinath Kartha was indeed central to example of ‘fragment complementation’ Nobel prize to Jerome Karle and Herbert the collagen story. demonstrated famously by Fred Richards Hauptman29. In 1959, Harker and Kartha and Paul Vithayathil, providing a dra- moved to the Roswell Park Memorial matic example of the importance of long- Institute, Buffalo, NY. But much remained Ribonuclease A range inter-residue interactions in main- to be done before a final assault on ribo- taining three-dimensional structure and nuclease. In Hauptman’s words6: ‘Due to Ribonuclease, a remarkably stable and enzymatic function27. the efforts of visiting crystallographers, abundant pancreatic enzyme played a Why have I digressed? It is merely to a number of critical problems were pivotal role in the development of pro- emphasize the centrality of the molecule solved during the Roswell Park years. M. tein chemistry and enzymology. The to the field of biochemistry and to revisit V. King solved the problem of dyeing the 1972 Nobel prize for chemistry25 recog- the first crystallographic structure deter- protein molecules in crystals and he pre- nized Christian Anfinsen ‘for his work mination of a protein in North America. pared ribonuclease in fourteen different on ribonuclease, especially concerning When Gopinath Kartha, Jake Bello and crystal forms. F. H. C. Crick discovered the connection between the amino acid David Harker reported the structure of the strong temperature dependence of the sequence and the biologically active con- ribonuclease on the pages of Nature in diffracted X rays from the protein crys- formation’. The Anfinsen experiment 1967 it was only the third protein to have tals mounted in sealed capillaries and established that code for directing three- been characterized at near atomic resolu- showed how to control it. V. Luzzati dimensional folding of proteins was tion28, after myoglobin (John Kendrew) showed how the intensity statistics were embedded in the sequence of the amino and lysozyme (David Phillips) and only related to the structure of the protein acids arranged along a polypeptide chain. the second enzyme to have its three- crystals and why the standard statistical The prize was shared by Stanford Moore dimensional structure revealed. The ribo- methods could not be applied in these and William Stein whose work on ribonuclease project in North America was cases. A. Tulinsky worked out the exact nuclease contributed ‘to the understand- initiated by David Harker at the Poly- structure of beryllium basic acetate and ing of the connection between chemical technic Institute of Brooklyn in 1950. It made it into a useful intensity standard. structure and catalytic activity of the was here that Gopinath Kartha joined G. Kartha developed new ways of using active centre of the ribonuclease molecule.’ him. Harker, a student of Linus Pauling, the diffraction data from non-centro- The 1984 Nobel prize in chemistry26 was was famous for his contributions to crys- symmetric crystals. A. de Vries showed awarded to R. Bruce Merrifield ‘for his tallography. Herbert Hauptmann, in his how anomalous dispersion effects could development of methodology for che- biographical memoir of Harker6 notes help in determining the structures of mical synthesis on a solid matrix’. Un- that ‘the Harker section made the Patter- crystalline proteins. J. Bello discovered doubtedly, what persuaded the Nobel son function useful’. The Harker–Kasper new ways of labeling ribonuclease crys- committee, on the utility of this funda- inequalities, developed during the deter- tals with heavy atoms. T. C. Furnas, Jr., mentally new method of synthetically mination of the structure of decaborane built their counter diffractometer, aided assembling peptide chains, was Merri- (B10H14), would become the forerunner by that artist in instrument construction field’s monumental solid-phase synthesis of the direct methods of phase determi- W. G. Weber. The stage was set to begin of ribonuclease A, a chemical tour de nation, which would eventually be recog- to collect X-ray crystallographic data force. Ribonuclease was also the first nized by the award of the 1985 chemistry from which the structure of ribonuclease

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Figure 5. a, A model of ribonuclease A from Kartha’s laboratory; b, Kartha lecturing at a conference in Madrid, Spain in April 1974.

could be determined.’ It is that structure Finally, in acknowledgements Kartha quote James Bryant Conant, President of determination which was accomplished not only credited his collaborators, on Harvard University for almost two dec- by Gopinath Kartha (Figure 5). Jake Bello, ribonuclease but thanked ‘Professor M. ades: ‘Each honest calling, each walk of in an obituary of Kartha, notes: ‘He was F. Perutz, who first showed me how to life has its own aristocracy, based on instrumental in resolving the structure of take X-ray diffraction photographs of excellence of performance.’ Gopinath the protein ribonuclease.’30 Wayne Hen- globular proteins, and, Professor G. N. Kartha’s molecules are a testimony to his drickson, in a tribute to Kartha, provides Ramachandran, who initiated me in the excellence in his chosen calling, crysta- an assessment31: ‘Kartha joined in the application of X-ray diffraction methods llography. middle of David Harker’s quest for the to fibrous proteins’. Reading Kartha’s The stories of Ramachandran and Kartha structure of ribonuclease, preceded by 1968 review may still be of benefit to take us back to a time when the shadowy many others, but in the end it was just he students entering the field of protein world of molecules was beginning to be with Jake Bello (crystallizer of the pro- chemistry today. illuminated by the power of X-ray dif- tein) who joined Harker in publishing the How then do I end this story of Gopi- fraction by crystals. It was a time when structure of ribonuclease A at 2 Å resolu- nath Kartha? The four structures I have in the experimental sciences sophistica- tion.’ In the first volume of the Accounts chosen to illustrate are all ‘firsts’ in tion of technique appeared less important of Chemical Research in 1968, in an many ways. They provide a view of the than the abilities to think analytically, article simply titled ‘Pictures of Pro- progress of crystallography in India in imaginatively, independently and inten- teins’, Kartha reflected on many issues32 the 1950s and early 1960s. In reading sely. The problems pursued contributed that have occupied protein chemists over Kartha’s work, it is clear that he played a to our understanding of molecules and the years that followed: Are protein con- key role in the birth of chemical crystal- nature; in Crick’s words, ‘mad pursuits’. formations in crystals and solution the lography in India. How would we de- The world of science has moved on but same? Is there a connection between pro- scribe Kartha the man? I can do no better reflecting on past achievement can often tein evolution and conformation? He was than borrow the words of Indira Kartha33: be inspirational.

prescient in drawing attention to Anfin- ‘….he was happy wherever he was; Pre- sen’s Harvey Lectures in 1965–66. His sidency College, Indian Institute of 1. Ramaseshan, S., Notes Rec. R. Soc. Lon- conclusion anticipated the decades of Science, Cavendish laboratory in Cam- don, 1996, 50(1), 115–127. discussion that would follow: ‘Whether bridge, NRC, Canada. In each place the 2. Banerjee, K., Nature, 1930, 125, 456. the conformation that the protein finally work was satisfying and the friends he 3. Kartha, G., Ph.D. thesis, Madras Univer- adopts is indeed a unique energy mini- had, understood him. It was difficult for sity, 1953. mum or whether it is only one of the most people to fathom him; for how 4. Kartha, G., Acta Crystallogr., 1952, 5, many local minima into which the pro- could such a brilliant well-known person 845–846. tein chain can be coaxed by gentle probe so simple? Once when we were with a 5. Kartha, G., Acta Crystallogr., 1952, 5, 549–550. dding from one minimum to another group of people, the evening wore off 6. Hauptman, H. A., Biogr. Mem., Nat. is one of the as yet unanswered but and Gopi Chettan was leaving. I heard Acad. Sci., 1998, 74, 127–140. hotly discussed questions in biology another scientist a newcomer ask “Is that 7. Sanjiva Rao, B., J. Chem. Soc. (London), 32 today.’ the real Dr. Kartha!” ’. She goes on to 1937, 853–855.

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8. Robinson, R., Biogr. Mem. R. Soc., Lon- 19. Pauling, L., Corey, R. B. and Branson, 31. Hendrickson, W. A., In A Tribute to Gopi- don, 1960, 5, 237–252. H. R., Proc. Natl. Acad. Sci. USA, 1951, nath Kartha, Indira Kartha and the Bahu- 9. Rao, P. L. N. and Verma, S. C. L., J. Sci. 37, 205–211. leyan Charitable Foundation, Ernakulam, Ind. Res., 1951, 10B, 184–185. 20. Watson, J. D. and Crick, F. H. C., 2007. 10. Rao, P. L. N., Krishnamurthy, D. V. and Nature, 1953, 171, 737–738. 32. Kartha, G., Acc. Chem. Res., 1968, 1, Verma, S. C. L., Die Naturwissenschaf- 21. Crick, F. H. C., What Mad Pursuit: A 374–381. ten, 1954, 66–67. Personal View of Scientific Discovery, 33. Kartha, I, in reference 31. 11. Kartha, G., Curr. Sci., 1954, 23, 8. Basic Books, New York, 1989, p. 67. ACKNOWLEDGEMENTS. I am most grate- 12. Sundara Rao, R. V. G., Padmanabhan, V. 22. Sarma, R., Ramachandran, Adenine ful to Dr Indira Kartha and Dr K. I. Varug- M. and Kartha, G., Curr. Sci., 1954, 23, Press, New York, 1998, pp 43–70. hese for their help in taking immense trouble 2167. 23. Dickerson, R. E., In The Proteins, Aca- in providing me with old documents, related 13. Ramachandran, G. N. and Raman, S., demic Press, 1964, vol. 2, 2nd edn, pp. to Kartha’s Bangalore days, for all details of Acta Crystallogr., 1959, 12, 957–964. 603–778. his career and Figures 2 and 5. I am grateful 14. Kartha, G., Ramachandran, G. N., Bhat, 24. Ramachandran, G. N. and Ambady, G. to Dr N. Yathindra for the copy of the letter H. B., Madhavan Nair, P., Raghavan, V. K., Curr. Sci., 1954, 23, 349–350. shown in Figure 4 and to Dr K. J. Sreeram, K. V. and Venkataraman, K., Tetrahe- 25. https://www.nobelprize.org/prizes/chemistry/ Director, CLRI Chennai for providing the dron Lett., 1963, 459–472. 1972/summary/ photographs in Figure 1.

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