Frederic M. Richards

Personal biography Richards was born on August 19, 1925, in New York City to George H. Richards and Marianna Middlebrook Richards. Both parents were from old New England families who had settled in Fairfield and New London, Connecticut, in the 1600s. The family usually spent summers in Connecticut, giving Richards an early affinity for the area which continued through his career at Yale University. He attended high school at Phillips Exeter Academy, and later recalled that "the excellent science department even permitted certain students the unsupervised run of the laboratories outside of class hours. This attitude played a strong role... in cementing our commitment to scientific careers." He and his wife had sailboats (Hekla 1 and 2) and an outboard-motor utility boat known as "Sally's Baage" He donated a 41-acre shoreline property to the Yale Peabody Museum Natural Areas, which they described as "one of the few natural forest areas left in the state." The property now has long-term protection for use in biological and geological research.

Research career

Two-component ribonuclease S system On December 2, 1957, at Yale University, Richards performed a simple experiment on the protein Ribonuclease A (RNase A) that helped change the scientific community's view of the physical nature of protein molecules. In an autobiographical piece, Richards wrote that "this discovery came as a surprise to the scientific community at that time.... In retrospect, this may have been the high point of my career in terms of excitement." This experiment showed that proteins maintain 3-dimensional order and tight binding between their interacting parts and that the structural information is inherent in the protein itself, foreshadowing both Anfinsen's later work showing that sequence determines structure and also the idea that hormones or other small molecules can bind tightly and specifically to proteins, Later, with Marilyn Doscher and Flo Quiocho, Richards demonstrated that ribonuclease S as well as carboxypeptidase were enzymatically active in the crystals, important evidence to silence doubts that the conformations of proteins in crystals are directly relevant to their biological activity in cells.

Ribonuclease crystal structure

Along with colleague Harold W. Wyckoff, who had worked on early research toward the myoglobin structure, the effort to solve the RNase S 3-dimensional structure was spearheaded by Richards. Done in 1966 and published in 1967, the analyses of RNase S and RNase A jointly made ribonuclease the third distinct protein structure to be determined by X-ray diffraction of crystals, after myoglobin/hemoglobin and hen-egg lysozyme, and the first to be done in the United States. Later, the Yale group collected more diffraction data, and in 1970 published the RNase S structure in full detail at 2.0 Å resolution . Coordinates for ribonuclease S were deposited into the international Protein Data Bank in 1973 as , among the first small set of macromolecular structures.

The black-and-white ribbon drawing above shows the large, twisted beta sheet (arrows) of ribonuclease, flanked by several alpha-helices (spirals). The shorter S-peptide piece is behind, starting at upper left with a helix and ending with the chain break (between residues 20-21) at lower right. Once the Folly had been constructed, he built an all-atom brass model of RNase S quite rapidly. and then Frodo.

Richards showed his sense of humor in a later review of developments in the use and construction of Richards boxes. He provided a "correction to the Original Bibliographic Citations," complete with diagrams, for a theatrical stage technique that used selective illumination and a sheet of plate glass inclined at 45° to give an illusion of the nymph Amphitrite rising from the sea and floating in air, or of an audience volunteer dissolving to a skeleton and back again. Richards ended that section by noting that "had this reference been known to the author in 1968 no further description of the 'folly' would have been required." and as the basis of the buried-surface-area method for estimating the energetics of protein/protein contacts.

introduced the Voronoi polyhedra construction to protein chemistry, a contribution reviewed more recently by Gerstein and Richards. This approach has been adopted by many others and has been put on a firm mathematical footing by the work of Herbert Edelsbrunner. With Jay Ponder in 1987, as part of an exploration of using internal packing of sidechains to enumerate the possible sequences compatible with a given protein backbone structure (a foreshadowing of protein engineering and design), Richards developed the first side-chain rotamer library. Increasingly detailed rotamer libraries, such as the Backbone-dependent rotamer library, have been made since then by other research groups, with some used primarily for structure validation and others for homology modeling or protein design. With Craig Kundrot, Richards investigated the effects of high pressure (1000 atmospheres) on protein structure, using hen-egg lysozyme crystals, finding that the structure was robust to such pressures apart from a quite modest compaction in size. In the 1990s, Richards and collaborators used a combination of theory and experiment to investigate how the well-packed interior of proteins can nevertheless accommodate mutations.

Other research areas In the 1970s, with a succession of students and postdocs, the lab developed a series of chemical, photochemical, and cross-link labels for determining the position and relationships of proteins in biological membranes , including glutaraldehyde and what was one of the two first general uses of the exceptionally tight interaction of biotin with avidin, The biotin–avidin system quickly became a central method in cell biology, immunology, and protein engineering, as well as electron microscopy.

With David Wishart and Brian Sykes, he developed the chemical shift index for NMR assignment of protein secondary structure ( & ). This is still considered a standard tool in the NMR field. Separately, around 1990, Homme Hellinga, with Richards, developed computational tools to design metal-binding sites into proteins, and used them to build a new metal site into thioredoxin.

Richards is named as a depositor on 27 crystal structure entries in the Protein Data Bank, including the now-obsoleted ribonuclease S , hen egg lysozyme , SH3 domains , the ion-channel-forming alamethicin , and mutants of ribonuclease S (e.g., ;), of Staphylococcal nuclease (e.g., ;), and of lambda repressor in complex with DNA .

Administration, mentoring, and outside activities The Department of Molecular Biophysics and Biochemistry ("MB&B") that Richards founded and chaired at Yale, which amalgamated the medical school Biochemistry and the university Molecular Biophysics departments, was considered to have "quickly gained pre-eminent stature." Richards was known as a highly valued mentor and friend to students, faculty, and colleagues, including a very supportive approach to women and African–Americans, according to Norma Allewell, quoted in a remembrance by Jim Staros. His colleague George D. Rose wrote that Richards' lectures were insightful, delivered with clarity and humor, and often deliberately provocative, and that Richards worked to improve the scientific community in general. He also lobbied, less successfully, for a let-up in overall publication pressure but an increased emphasis on a few first-class papers, by having promotion committees only consider a list of 12 key papers. 1955, joined Yale faculty, in Biochemistry at the Medical School 1969–73, founding chair of the Department of Molecular Biophysics and Biochemistry at Yale 1972, President of the Biophysical Society 1976–91, Director of the Jane Coffin Childs Fund for Medical Research 1988, Protein Society – Stein and Moore Award 1992, Member, American Philosophical Society 1995, Connecticut Medal of Science