Oleg Ptitsyn 1929–1999

Oleg Ptitsyn was a pioneer in protein folding studies: his discovery of molten globule folding intermediates revolutionized the field. He died in England on March 22, 1999, after a heart attack. Oleg Ptitsyn was born in St. Petersburg ~Leningrad! on July 18, 1929, and took his M.Sc. in Molecular Physics at the University of Leningrad at the age of 22. He remained in Leningrad, at the Institute of High Molecular Compounds, first taking his Ph.D. in 1954 and then his D.Sc. in 1963 in physical and mathematical sciences. In 1967, he became Deputy Director of the Institute of Protein Research and simultaneously Head of the Laboratory of Protein Physics at Pushchino, at the Academy of Sciences Institute for Protein Research. He retained his position at Pushchino after becoming in 1992 a visiting member of the NIH Laboratory of Mathematical Biology, in the section of Robert Jernigan. In the early 1970s Oleg Ptitsyn was one of a small band of scientists dispersed around the world, each intent on solving the protein folding problem in his or her own way. Colleagues in other fields, who generally viewed the folding problem as insoluble, thought these people were nutty and frequently told them so. Chris Anfinsen, Charles Tanford, and John Schellman, who had played a major role in setting up the field, were moving on to new interests by the mid-1970s. Harold Scheraga wanted to predict protein structures from amino acid sequences by energy minimization. Kurt Wüthrich wanted to track the folding process by NMR, but he became diverted to determining protein structures by NMR. Fred Richards and also Jane and Dave Richardson were deciphering the secrets of packing arrangements in protein structures. Martin Karplus was developing a kinetic mechanism of folding that could solve the Levinthal paradox. Tom Creighton was isolating coval ntly trapped intermediates by coupling folding to disulfide bond formation, while I was intent on characterizing kinetic folding intermediates in reactions not involving disulfide bonds. Cy Levinthal and Michael Levitt, like Oleg Ptitsyn, wanted to predict protein structures by first predicting their folding pathways. In this group Oleg Ptitsyn was unique in having a strong background in polymer physics. At the age of 35 he had co-authored with T. M. Birstein a book entitledConformations of Macromolecules~later published in English, Birstein & Ptitsyn, 1966 !, which summarized their theoretical studies on the relation between polymer flexibility and local order in the polymer backbone. In 1967 Oleg Ptitsyn moved to the Laboratory of Protein Physics at Pushchino, near Moscow. He and his colleague Alexey Finkelstein very early proposed a method for predicting protein secondary structure from sequence ~Ptitsyn & Finkelstein, 1970 !, a method similar in character to the popular Chou–Fasman method of 1974. Next he proposed a model for how proteins fold ~Ptitsyn, 1973!. His model might be called hierarchic folding today, but recently Ptitsyn preferred to call it the framework model, a term coined by Peter Kim and myself. In his model, folding starts in the backbone by first forming secondary structures, a-helices andb-strands, which then interact by nonspecific interactions, the hydrophobic interaction and hydrogen bonds, to form more advanced folding intermediates. Ptitsyn emphasized that in his model each stage of the folding process stabilizes the major conformation already present so that only native-like backbone structure is present, in addition to unfolded segments, at all stages of folding. To show the potential of his model, Ptitsyn and Rashin used it to predict the dominant folding pathway of apomyoglobin ~myoglobin without the heme !, which then yields the structure of the native protein as the end product of this pathway ~Ptitsyn & Rashin, 1975!. They took the locations of the helices as being known from the X-ray structure and they assumed that each pair of neighboring major helices could act as a “crystallization center” initiating the growth of the overall structure. They predicted a major folding pathway, which yielded a product resembling native myoglobin ~without the heme !. Although later work did not confirm this prediction of the dominant folding pathway, nevertheless their paper was highly influential in forecasting the course of future work. Photo of Oleg Ptitsyn courtesy of Mrs. Irina Ptitsyna. Protein Science~1999!, 8:1562–1563. Cambridge University Press. Printed in the USA. Copyright © 1999 The Protein Society