Pittsburgh Diffraction Conference '05

Professor Muttaiya Sundaralingam (1931-2004)

thoughts of a former student

From a student’s perspective, Professor Muttaiya Sundaralingam, universally known as ‘Sunda’, was a consummate scientist, both rigorously disciplined and highly creative. Following his Ph. D. work with G. A. Jeffrey at the University of Pittsburgh, and a stage of his career at Case Western Reserve University, he moved to the University of Wisconsin, Madison, in 1970 to direct a laboratory focused on the structures of nucleic acids and their components. He was chemical crystallographer in the classical sense, using high resolution crystal structures to deduce principles about the behavior of molecules from their bond distances, angles, torsions, hydrogen bonding, conformation, and crystal packing. He developed this approach through training with George Jeffrey where the focus was often on carbohydrates. Underlying concepts in this research were the value of atomic resolution, the use of crystals to infer chemical interactions, and the need to understand the subtleties and details of hydrogen bonding.

Sunda subsequently employed crystallography in a systematic, virtually exhaustive manner to the components of nucleic acids, the bases, sugars, nucleosides, and nucleotides, of all kinds, and to polynucleotides. This research was inspired by Linus Pauling’s analysis of protein structure, and the principle that though precise definition of the building blocks, one could deduce the structure of the biological macromolecule. Sunda’s special gift was to visualize and understand stereochemistry, and so he was not afraid to apply the results of his crystal structures to the complicated nucleotide components of nucleic acids. One of his fundamental contributions was to identify the conformational preferences of furanose sugars, in terms of a newly defined pseudorotation angle. Using this analysis, he was able to unravel the observed conformations of nucleosides and nucleotides, and develop the ‘rigid nucleotide hypothesis’ based on preferred C2¢ endo and C3¢ endo sugar puckers. His work further defined favored ranges of torsion angles for all of the sugar and phosphate bonds in the polynucelotide, and the preferred torsion angles about the glycosidic bonds of the bases. In concert with stereochemical analysis from crystal structures, Sunda always built models, and he used the models to infer energy landscapes, especially for helical nucleic acids, through rigorous theoretical calculations. In other words, he extended his understanding of the repeating units to the macromolecule and its dynamics. Simultaneously, this led him to study crystal structures of transfer RNAs, and RNA and DNA duplexes. It is impossible to imagine a contemporary understanding of nucleic acid structure without Sunda’s fundamental insights. He reduced the problem of stereochemical analysis of polynucleotides to simple rules and conformational preferences, much as Ramachandran did for the analysis of protein structure.

The 1999 Pittsburgh Diffraction Conference at Ohio State University was organized to honor Sunda upon his retirement. At that time, a compendium bibliography of Sunda’s 330 scientific publications was presented. In his own presentation, entitled ‘From Nucleic Acids to Proteins – 40 years of Structural Molecular Biology’ he provided an overview of his own career as he focused on the nature of base-base interactions in nucleic acid structures. In his lecture he reviewed many types of base-base hydrogen bonding interactions and their role in RNA tertiary structure and recognition. The lecture was exemplary of Sunda’s approach to science: he presented a wide diversity of crystal structures and models, analyzed the complexities seen at high resolution, emphasized the nature of these molecular interactions and hydrogen bonding patterns in folded RNA, and provided a synthesis.

Sunda’s life influenced many people, and he had many scientific collaborators. His close colleague of many years, N. Yathindra, has published an excellent and lengthy review of Sunda’s life and work in Acta Cryst. (vol. D61, pp. 845-849, 2005). As Yathindra points out, ‘Sunda attracted a number of bright students and post docs through his charismatic discourse on the unique ability of X-ray diffraction techniques to visualize biological macromolecules’. Personally, I was attracted by exactly such ‘charismatic discourse’ when as a first year graduate student Sunda enlightened me as to how biochemical molecules could be examined in three dimensions. At that time, in his lab in the 1970s, a number of graduate students were set to work on projects that would influence their careers, especially through a passion for solving structures. Sunda, and other scientists he attracted to his group, in particular S. T. Rao and R. K. McMullan, insisted on and taught crystallographic principles, while the goal was always to solve the next interesting structure. As a mentor, Sunda provided guidance by creating the environment, and generating the energy to ask the interesting questions, but he also left his students to work out the details of the problem on their own. This is turn created an atmosphere that fostered a great deal of interaction and shared learning. Personally, Sunda was a gracious and patient advisor, and fostered the careers of all of his students with care. He and his wife, Indrani, hosted many dinners, picnics and parties, including everyone in his laboratory into his extended family.

This year’s special Sunda Symposium at the Pittsburgh Diffraction Conference will include presentations from several of Sunda’s students who shared their graduate careers in his laboratory in the period of the 1970s. The aim is to demonstrate that at one time Sunda's lab harbored a special collection of students, who have gone on to do a wide variety of interesting research, all connected in some way to the crystallographic inspiration he provided. This on-going research he inspired, and the careers Sunda mentored, is a testimony to his contribution to crystallography.

Dave Stout

The Scripps Research Institute

9/26/05