DuPont Central Research (1985-1991)
In the early 1990’s DuPont decided to initiate a major effort in biotechnology, mainly through the expansion of the Central Research and Development (CRD) facility in Wilmington DE. I was fortunate to be part of the effort in what in retrospect were halcyon years of creative scientific research.
Cytochrome C- Cytochrome b5
Complex Molecular Dynamics
Our group at DuPont CRD was among the first to perform simulations of biological complexes whose properties could be correlated with intermolecular electron transfer experiments carried out in solution.
Complex Molecular Dynamics
Our group at DuPont CRD was among the first to perform simulations of biological complexes whose properties could be correlated with intermolecular electron transfer experiments carried out in solution.
Streptavidin - Chelator : DNA Complex
State-of-the-Art macromolecular modeling facilities at DuPont CRD enabled our group to make accurate molecular representations of many biological macromolecular complexes commonly used in biomedical research.
State-of-the-Art macromolecular modeling facilities at DuPont CRD enabled our group to make accurate molecular representations of many biological macromolecular complexes commonly used in biomedical research.
Some Protein X-Ray structures determined at DuPont CRD
Thrombin Inhibitor Complexes
Pro-Phospholipase
Avian Myoblastosis Protease
Phospholipase A2
Interleukin 1Beta
Streptavidin-Biotin Complex
Protocatachuate Dioxygenase
At about the time that the Protein Engineering Group at Genex was winding down, I became aware of an interesting opportunity at DuPont Central Research Department (CRD at the Experimental Station) in Wilmington DE. Basically, DuPont had decided to make a big push into biotechnology and had given Mark Pearson a broad charter to develop the basic resources to drive a diverse portfolio of research efforts. In considering the job in CRD, I was particularly concerned with the nature of the computing environment, since I had established the importance of state-of-the-art computing resources for structure determination and computational modeling while at Genex. I was set up with an interview with Paul Meakin, who at that time was producing a wealth of new papers on computational fractal behavior in physical systems in Phys Rev Letters. He convinced me to join simply because I figured that if an individual as smart and idiosyncratic as Paul was happy there, then so I could be.
As it evolved, I was able to recruit many members of the protein Engineering Division that I had assembled at Genex to CRD, including Pat Weber, Doug Ohlendorf, Michael Pantoliano, and James Matthew. At that time (1985) DuPont CRD was structurally organized around very small groups with a Principle Investigator and a technician constituting the prototype research unit. My operation was assigned to the 228 Building on the Experimental Station. The 228 building had originally gained fame as the building where Wallace Carothers had carried out the purification of his reagents as necessary to sustain the chain polymerization of nylon. Subsequently it had become the location for many of the scientists that were doing structural characterization work at DuPont CRD. This was in fact a great environment, since we were in daily contact with small molecule crystallographers like Joe Calabrese and Dick Harlow who were working on interesting structures like high-Tc superconductors. We established a facility that included a rotating anode X-ray set with a Xentronics area detector (we had pioneered the development of the instrumentation while at Genex), as well as a DEC Vax 11-780 (and later a STAR-100 array processor), and a suite of Evans and Sutherland graphics terminals. I was especially lucky to recruit Richard Hilmer from another group at CRD, since he was an expert at programming the Evans and Sutherland graphics systems using their arcane proprietary programming language.
We entertained a diverse group of material scientists from throughout DuPont operating departments and CRD who were interested in looking at diffraction patterns using our Xentronics area detector and high intensity rotating anode X-ray source. We also used the codes built by Dick Hilmer to model many complex polymer systems of interest to DuPont operating departments.
Our main efforts in protein crystallography were driven by Doug Ohlendorf, Barry Finzel, Karl Hardman, and Patricia Weber. This group produced a lot of significant science including numerous structures (streptavidin, several serine proteases, phospholipase A2, protocatachuate dehydrogenase, IL1b, etc.) and novel methods for protein modeling using recurrent fragment methods (eg. FRAGL and PROBIT).
As it evolved, I was able to recruit many members of the protein Engineering Division that I had assembled at Genex to CRD, including Pat Weber, Doug Ohlendorf, Michael Pantoliano, and James Matthew. At that time (1985) DuPont CRD was structurally organized around very small groups with a Principle Investigator and a technician constituting the prototype research unit. My operation was assigned to the 228 Building on the Experimental Station. The 228 building had originally gained fame as the building where Wallace Carothers had carried out the purification of his reagents as necessary to sustain the chain polymerization of nylon. Subsequently it had become the location for many of the scientists that were doing structural characterization work at DuPont CRD. This was in fact a great environment, since we were in daily contact with small molecule crystallographers like Joe Calabrese and Dick Harlow who were working on interesting structures like high-Tc superconductors. We established a facility that included a rotating anode X-ray set with a Xentronics area detector (we had pioneered the development of the instrumentation while at Genex), as well as a DEC Vax 11-780 (and later a STAR-100 array processor), and a suite of Evans and Sutherland graphics terminals. I was especially lucky to recruit Richard Hilmer from another group at CRD, since he was an expert at programming the Evans and Sutherland graphics systems using their arcane proprietary programming language.
We entertained a diverse group of material scientists from throughout DuPont operating departments and CRD who were interested in looking at diffraction patterns using our Xentronics area detector and high intensity rotating anode X-ray source. We also used the codes built by Dick Hilmer to model many complex polymer systems of interest to DuPont operating departments.
Our main efforts in protein crystallography were driven by Doug Ohlendorf, Barry Finzel, Karl Hardman, and Patricia Weber. This group produced a lot of significant science including numerous structures (streptavidin, several serine proteases, phospholipase A2, protocatachuate dehydrogenase, IL1b, etc.) and novel methods for protein modeling using recurrent fragment methods (eg. FRAGL and PROBIT).
John Wendoloski also joined my group and we began to extensively use the AMBER molecular dynamics code to simulate a number of polymer and biological systems such as protein electron transfer complexes and micelles. I was also joined by Zelda Wasserman who had joined DuPont CRD from Bell Labs where she worked as a computational scientist. Zelda and I worked on simulations of elastin to establish the factors responsible for the elastomeric restoring force.
One of the great features of DuPont CRD was their visiting summer program for undergraduate students. My great friend, Clarence Schutt, was a Professor of Chemistry at Princeton who directed me to some of his most talented students as summer interns in our group. These included Lars Geneiser and Steve Kimatian, who respectively coauthored significant publications in lysozyme crystal packing and micelle molecular dynamics.
One of the more interesting projects that we were involved in was a collaboration with John O’Brien in the (then) DuPont Polymer Products Division (PPD). DuPont was of course known for its invention of Nylon, Kevlar, Kapton, Lycra and other polymers that had wide commercial application. Nevertheless, biological polymers (most notably spider dragline silk and elastin) possessed highly desirable properties that were not observed in synthetic polymers. This motivated a number of computational studies to model the structures and simulate the properties of natural and synthetic polymers, ranging from Kapton to elastin.
In addition to modeling and computational studies, PPD decided to support the recombinant biosynthesis of several designer biopolymers whose production was contracted out to Protein Polymer Products, a biotech company in San Diego CA. Based on molecular design inputs, several gene constructs were developed by Ron Hoess, a molecular biologist in CRD. These included silk-like polymers as well as a construct based on the adenovirus tail spike structure. Although these polymers could be spun into fibers, it proved difficult to replicate the mechanical properties of the naturally occurring materials. Subsequently it has been determined that the properties of the natural materials involve complex structural features that are not present in the simpler repetitive polypeptide sequences synthesized at DuPont.
Throughout this period, our group had assisted numerous efforts in structure-based compound design in support of both the DuPont Agricultural Products Department and DuPont-Merck Pharmaceuticals. However, by the beginning of 1991, DuPont had decided to downsize CRD and to shift more resources to the operating departments. As a result, my group was moved to DuPont Merck Pharmaceuticals and asked to focus on structure-based drug design. Although we would miss the many opportunities to work closely with materials scientists, advances in computational methods and high-throughput data collection had made iterative protein structure analysis, performed in real-time to direct support of chemical lead optimization programs, a reality. Consequently we were enthusiastic about the potential for the new effort.
In early 1991 I left DuPont CRD to build a new computational design and structure determination group at the newly established Sterling-Winthrop Pharmaceutical Research Division (SWPRD) in Collegeville PA. Again, I was able to assemble an outstanding group of scientists. My tenure at SWPRD was cut short when I was offered an opportunity to build my own company, which materialized as 3–Dimensional Pharmaceuticals.