Dale E. Tronrud

Member of the Coronavirus Structural Task Force
Contact me at det101@daletronrud.com

X-ray crystallography is a technique where a crystal of a material is illuminated by a beam of x-rays. The scattering of those x-rays are measured and used to determine the arrangement of atoms in that crystal. The methods for determining the structure of large molecules, such as proteins and DNA, are of particular interest to me.I have developed a number of novel methods, written papers describing them, and incorporated these ideas into the TNT refinement package. Unfortunately quite a few of my ideas have been implemented in TNT without ever having been written up in papers. It's my own fault, of course.

I have worked on a number of crystal structures myself. Not many, but they are good ones. Using data collected by Roger Fenna and Mike Schmid, I refined a model for the FMO protein from the Green Sulfur Bacteria formerly known as Prosthecochloris aestuarii 2K. This 1.9 Å model stood as the highest resolution model of a chlorophyll containing protein until 2004. In 2009 I published and deposited a 1.3 Å model of this same protein (PDB code: 3EOJ) and regained the title of highest resolution chlorophyll containing protein.

Since none of the refinement programs available in the 1980's could handle the complexities of a bacteriochlorophyll-a molecule I needed to use Lynn Ten Eyck's TNT refinement program, which is how I got into that business.

I have also worked on a number of inhibitor complexes with the endopeptidase Thermolysin. Thermolysin was a great system to work with because one could soak in rather large inhibitors (the equivalent of four amino acids in size). We worked with a variety of inhibitors to probe various ideas for the design of better inhibitors, and by analogy, better drugs.

While I had been working in Brian Matthews' lab for many years, that lab shut down in 2009. I worked for Andy Karplus at Oregon State University for the next seven years. The main thrust of my work there was the exploration of the practical consequences of using his new library of standard values for bond lengths and angles in the peptide backbone.

I'm currently working on projects of my own. I have collected a lot of ideas over the years and now seems a good time to work through them and get them published (if they end up making sense!). The list includes quite a number of ideas for improving the crystallographic part of refinement, but I intend to contine some of the conformation-dependent stereochemical restraint work I started in the Karplus Lab.

Near the start of the pandemic in 2020 I signed up with the Coronavirus Structural Task Force. This is a group of structural biologists who are organizing, assessing, correcting, and distributing information about the SARS-CoV-2 virus. I have done some work on various parts of NSP3 but also pontificate on the ugly and dark history of protein crystallography.

I am maintaining connections to labs both at the University of Oregon and Oregon State University, despite the general animosity felt by the alumni of those two institutions.

TNT

TNT is a package of programs used to optimize the fit of a model of a protein/nucleic acid to X-ray diffraction data while maintaining quality bond lengths, angles, and other good things.

Method Papers

(html) (pdf) An Efficient General-Purpose Least-Squares Refinement Program for Macromolecular Structures. Tronrud, D.E., Ten Eyck, L.F. and Matthews, B.W. Acta Cryst. (1987). A43, 489-501
(html) (pdf) Conjugate-Direction Minimization - An Improved Method for the Refinement of Macromolecules. Acta Cryst. (1991). A48, 912-916
(html) (pdf) Methods of Minimization and their Implications. "Proceedings of the CCP4 Study Weekend", 1994
(html) (pdf) Knowledge-Based B-Factor Restraints for the Refinement of Proteins, J App Cryst. (1996). 29(2), 100-104
(html) (pdf) The Limits of Interpretation, "Proceedings of the CCP4 Study Weekend", 1996
(html) (pdf) The Joint Refinement of Inhibitors of Thermolysin, in Proceedings of the Macromolecular Crystallographic Computing School, Eds Phil Bourne, and Keith Watenpaugh, 1996
(html) (pdf) The TNT Refinement Package. in Macromolecular Crystallography, Part B, Eds Charlie Carter, and Robert Sweet, Volume 277 in Methods in Enzymology, pp 306-319, 1997
(html) (pdf) The Efficient Calculation of the Normal Matrix in Least-Squares Refinement, Acta Cryst. (1999). A55, 700-703
(html) (pdf) Introduction to Macromolecular Refinement, "Proceedings of the CCP4 Study Weekend", Acta Cryst. (2004). D60, 2156-2168
(html) (pdf) Including Novel Restraints Supplied by the User to the TNT Refinement Package, Commission on Crystallographic Computing Newsletter. (2004). 4, August, 52-58
(html) (pdf) Using a Conformation-Dependent Stereochemical Library Improves Crystallographic Refinement of Proteins. Tronrud, D.E., Berkholz, D.S. and Karplus, P.A., Acta Cryst. (2010). D66, 834-842.
(html) (pdf) A Conformation-Dependent Stereochemical Library Improves Crystallographic Refinement even at Atomic Resolution. Tronrud, D.E. and Karplus, P.A., Acta Cryst. (2011) D67, 699-706.
(html) (pdf) A Complete Fourier-Synthesis-Based Backbone-Conformation-Dependent Library for Proteins. Tronrud, D.E. and Karplus, P.A., Acta Cryst. (2021) D77, 249-266.

Structure Papers

(pdf) Structural Analysis of the Inhibition of Thermolysin by an Active-Site-Directed Irreversible Inhibitor, Holmes, M.A., Tronrud, D.E. and Matthews, B.W., Biochemistry, 22, 236-240 (1983) (I performed the refinement of this inhibitor using the earliest version of TNT. The program to produce Fig 4 was the first program I wrote in the lab.)
(pdf) Structure and x-ray amino acid sequence of a bacteriochlorophyll a protein from prosthecochloris aestuarii refined at 1.9 Å resolution, Tronrud, D.E., Schmid, M.F. and Matthews, B.W., J. Mol. Biol. 188, 443-454 (1986). (Mike grew the crystals, collected the diffraction data and performed the initial refinement. I finished the refinement, which took a considerable amount of work including massive development of the TNT refinement package.)
(pdf) Slow- and fast-binding inhibitors of thermolysin display different modes of binding: Crystallographic analysis of extended phosphonamidate transition-state analogues, Holden, H.M., Tronrud, D.E., Monzingo, A.F., Weaver, L.H. and Matthews, B.W., Biochemistry, 26, 8542-8553 (1987) (Art collected the data and began the refinement of ZG^PLL while Hazel and I worked together to collect the data for ZF^PLA and finish the refinement of both inhibitors.)
(---) Structures of two thermolysin-inhibitor complexes that differ by a single hydrogen bond, Tronrud, D.E., Holden, H.M. and Matthews, B.W., Science, 235, 571-574 (1987) (Hazel and I worked together closely on these two inhibitors.)
(pdf) Analysis of the Effectiveness of Proline Substitutions and Glycine Replacements in Increase the Stability of Phage T4 Lysozyme, Nicholson, H., Tronrud, D.E., Becktel, W.J. and Matthews, B.W., Biopolymers, 32, 1431-1441 (1992) (My only contribution to this paper is the survey of phi-psi angles of proline and pre-proline residues.)
(pdf) Refinement of the Structure of a Water-Soluble Antenna Complex from Green Photosynthetic Bacteria by Incorporation of the Chemically Determined Amino Acid Sequence, Tronrud, D.E. and Matthews, B.W., in The Photosynthetic Reaction Center, Volume 1, 13-21 (1993) (This chapter describes the results of additional refinement of the FMO protein based on the amino acid sequence produced by Roger Fenna's lab. The same 1.9 Å data set was used.)
(---) Refined structure of Cro repressor protein from bacteriophage λ suggests both flexibility and plasticity, Ohlendorf, D.H., Tronrud, D.E. and Matthews, B.W.,J. Mol. Biol. 280, 129-136, (1998) (I completed the refinement of this structure.)
(pdf) The Structural Basis for the Difference in Absorbance Spectra for the FMO Antenna Protein from Various Green Sulfur Bacteria, Tronrud, D.E., Wen, J., Gay, L. and Blankenship, R.E., Photosyn. Res. 100(2), 79-87, (2009) (I designed this project, collected the diffraction data and analyzed the results.)
(---) Lessons from the Lysozyme of Phage T4, Baase, W.A., Liu, L., Tronrud, D.E. and Matthews, B.W., Protein Sci. 19, 631-641, (2010) (I helped collect the information for this paper and dug up and deposited the structure factors for nearly all the T4 lysozyme structures solved in the Matthews lab.)
(---) Iron-Containing Urease in a Pathogenic Bacterium, Carter, E.L., Tronrud, D.E., Taber, S.R., Karplus, P.A. and Hausinger, R.P., PNAS 108(32), 13095-13099 (2011). (I solved the structure with Molecular Replacement, refined the model, and prepared the figures of the structure.)
(pdf) Reinterpretation of the electron density at the site of the eighth bacteriochlorophyll in the FMO protein from Pelodictyon phaeum, Tronrud, D.E., Allen, J.P., Photosynth Res 112(1), 71-74 (2012) (Jim and I worked together closely on the description of the new model.)

PhD Thesis

(pdf) The Refinement of Macromolecular Structures, Tronrud, D.E. (1986) (12MB, you didn't expect it to be small, did you?)

PowerPoint Presentations

Introduction to Macromolecular Refinement, York Refinement Workshop, January 2001
Stereochemical Dictionaries, York Refinement Workshop, January 2001