The long-term goal of the Richardson lab is to contribute to a deeper understanding of the 3D structures of proteins, including their description, determinants, folding, evolution, and control. This has now been broadened to include RNA structures. Our approaches include structural bioinformatics, macromolecular crystallography, molecular graphics, analysis of structures, and methods development, currently focussed on the improvement of structural accuracy.
Following on two of the earliest protein crystallographic structures (Staphylococcal nuclease and Cu,ZN superoxide dismutase), our continuing analysis and comparison of protein structures then led to an early classification system, new overall folds (such as the Greek key beta barrel, and what is now called the SS beta cross), and description of many new small-scale features (such as right-handed crossovers, beta bulges, helix N-caps and C-caps, and cisPro touch-turns). We now also analyze structural motifs in RNA, including an all-angle definition of conformers for RNA backbone.
We develop methods for representing protein structure, most notably the hand drawings that popularized ribbon schematics and formed the basis for the present computer ribbon drawings. We develop software to fill what we see as unmet needs, most notably kinemages (molecular graphics optimized for the communication of specific ideas in 3D) and the associated Mage and KiNG display programs, free software on Mac, PC, and Linux, widely used for teaching and databases as well as for research. Mage and KiNG incorporate many functions for analyzing and rebuilding macromolecules, including the "Backrub" tool for making realistic local movements in protein backbone.
We were among the first groups to do protein de novo design and made designs in all 4 of the major tertiary-structure types, using complex, native-like sequences (e. g., betabellin, Felix, babarellin, and SScorin). We introduced the concept of negative design, and we first pointed out the general problem of the more-or-less molten nature of most fully de novo designs. In order to treat internal packing in quantitative detail, we developed an all-atom contact algorithm to quantify and visualize the geometric details of molecular interaction; it uses all explicit H atoms and a very small probe sphere to show those surface patches where atoms are within 0.5 Å of exact van der Waals contact. This method gives a sensitive description of packing quality within or between molecules, for use in protein or drug design, for understanding structural features and interactions, and for designing non-disruptive mutations. All-atom contact analysis, along with crystallographic B-factors, allowed us to construct much-improved libraries and data distributions for protein sidechain rotamers and Ramachandran phi,psi backbone angles. All of these validation analyses can be run interactively on the MolProbity web service, including optimized hydrogen addition and automated correction of "flipped" sidechain amide or histidine orientations.
All-atom steric clashes are a powerful and sensitive way of finding problems in molecular structures, and even of suggesting how to make corrections. As part of the SECSG structural genomics effort, we used MolProbity diagnosis along with rebuilding and refinement on 29 SECSG structures, producing modest improvements in traditional crystallographic measures (R, Rfree, geometry, real-space residual) and dramatic order-of-magnitude improvements in all-atom clashscore and rotamer and Ramachandran outliers. We are now working to extend applicability to RNA and to NMR structures, and, as part of the PHENIX software team, to further integrate and automate these techniques in crystallography. A long-term vision is to enable the determination of accurate models even from low-resolution data.
For more details, see our kinemage web site at http://kinemage.biochem.duke.edu/, where all our software is available free and open-source, as well as datasets and examples. There is a service called MolProbity where you can run our structure validation tools on an uploaded file of your own or one chosen from the PDB or NDB, and display the results directly on-line in KiNG.
Associate Professor Materials Science & Engineering, NC State
thlabean AT ncsu.edu
Simon Lovell
Faculty of Life Sciences Univ of Manchester, UK
simon.lovell AT man.ac.uk
Michael Word
Open Eye Software (retired) Santa Fe, NM
word27605 AT gmail.com
Selected Publications
"The importance of residue-level filtering, and the Top2018 best-parts dataset of high-
quality protein residues".
Williams C, Richardson D, Richardson J.
(2022)
Protein Science
1
290-300
doi: doi.org/10.1002/pro.4239
"Seeing the PDB".
Richardson JS, Richardson DC, Goodsell DS.
(2021)
J Biol Chem
296, 100742
??-??
doi: doi.org/10.1016/j.jbc.2021.100742
"Making the invisible enemy visible".
Croll TI, Diederichs K, Fischer F, Fyfe C, Gao H, Harrell S, Joseph AP, Kandler L, Kippes O, Muller K, Kirsten F, Nolte K, Payne A, Santoni G, Stub S, Reeves M, Richardson J, Tronrud D, Williams C, Thorn A.
(2021)
Nat Struct Molec Biol
28
404-408
doi: 10.1038/s41594-021-00593-7
"How Algorithms from Crystallography are Helping Electron Cryo-Microscopy".
Adams PD, Liebschner D, Terwilliger TC, Afonine PV, Richardson JS.
(2021)
Single-particle CryoEM of Biological Macromolecules
chapter 6.5
??-??
doi:
"Cryo-EM model validation recommendations based on outcomes of the 2019 EMDataResource challenge".
Lawson CL, Kryshtafovych A, Adams PD, Afonine PV, Baker ML, Barad BA, Bond P, Burnley T, Cao R, Cheng J, Chojnowski G, Cowtan K, Dill KA, DiMaio F, Farrell DP, Fraser JS, Herzik MA Jr, Hoh SW, Hou J, Hung LW, Igaev M, Joseph AP, Kihara D, Kumar D, Mittal S, Monastyrskyy B, Olek M, Palmer CM, Patwardhan A, Perez A, Pfab J, Pintilie GD, Richardson JS, Rosenthal PB, Sarkar D, Schäfer LU, Schmid MF, Schröder GF, Shekhar M, Si D, Singharoy A, Terashi G, Terwilliger TC, Vaiana A, Wang L, Wang Z, Wankowicz SA, Williams CJ, Winn M, Wu T, Yu X, Zhang K, Berman HM, Chiu W.
(2021)
Nat Methods
18
156-164
doi: 10.1038/s41592-020-01051-w
"Improving SARS-CoV-2 structures: Peer review by early coordinate release".
Croll TI, Williams CJ, Chen VB, Richardson DC, Richardson JS.
(2021)
Biophys J
120
1085-1096
doi: 10.1016/j.bpj.2020.12.029
"New Tools in MolProbity Validation: CaBLAM for cryoEM backbone, UnDowser to rethink "waters", and NGL Viewer to recapture online 3D graphics".
Prisant MG, Williams CJ, Chen VB, Richardson JS, Richardson DC.
(2020)
Protein Sci
29
315-329
doi: 10.1002/pro.3786
"Improved chemistry restraints for crystallographic refinement by integrating Amber molecular mechanics into Phenix".
Moriarty NW, Janowski PA, Swails JM, Nguyen H, Richardson JS, Case DA, Adams PD.
(2020)
Acta Cryst
D76
51-62
doi: 10.1107/S2059798319015134
"Art and Analogy Help Scientists "See" Big Biological Molecules in 3D".
Richardson JS.
(2018)
SciArt Mag
33
1-6
doi: ??
"Cis-nonPro peptides: Genuine occurrences and their functional roles".
Williams CJ, Videau LL, Hintze BJ, Richardson JS, Richardson DC.
(2018)
bioRxiv
??
??-??
doi: 10.1101/324517
"MolProbity: More and better reference data for improved all-atom structure validation".
Williams CJ, Hintze BJ, Headd JJ, Moriarty NW, Chen VB, Jain S, Prisant MG Lewis SM, Videau LL,
Keedy DA, Deis LN, Arendall WB III, Verma V, Snoeyink JS, Adams PD, Lovell SC,
Richardson JS, Richardson DC.
(2018)
ProtSci
27
293-315
doi: 10.1002/pro.3330, PMC5734394
"Assessment of detailed conformations suggests strategies for improving cryoEM models:
helix at lower resolution, ensembles, pre-refinement fixups, and validation at a
multi-residue length scale".
Richardson JS, Williams CJ, Videau LL, Chen VB, Richardson DC.
(2018)
J Struct Biol (CryoEM Challenge special issue)
204
319-328
doi: 10.1016/j.jsb.2018.08.007
"Constructing atomic structural models into cryo-EM densities using molecular dynamics -- Pros and Cons".
Wang Y, Shekhar M, Thifault D, Williams C, Mcgreevy R, Richardson J, Singharoy A, Takhorshid E.
(2018)
J Struct Biol (CryoEM Challenge special issue)
204
301-312
doi: 10.1016/j.jsb.2018.08.003
"Model validation -- local diagnosis, correction, and when to quit".
Richardson JS, Williams CJ, Hintze BJ, Chen VB, Prisant MG, Videau LL, Richardson DC.
(2018)
Acta Cryst D
74
132-142
doi: from CCP4 Study Weekend 2017) PMC5947777
"Cis-nonPro peptides: Genuine occurrences and their functional roles".
Williams CJ,Videau LL, Hintze BJ, Richardson JS, Richardson DC.
(2018)
https://www.biorxiv.org/content/early/2018/05/17/324517
doi:
"Broad analysis of vicinal disulfides: Occurrences, conformations with cis or with trans peptides, and functional roles including sugar binding".
Richardson JS, Videau LL, Williams CJ, Richardson DC.
(2017)
J Mol Biol
429
1321-1335
doi:
"MolProbity's ultimate rotamer-library distributions for model validation".
Hintze BJ, Lewis SM, Richardson JS, Richardson DC.
(2016)
Proteins: Struc Func Bioinf
84
online since Mar 28
doi: 10.1002/prot.25039 (open access)
"Computational methods for RNA structure validation and improvement".
Jain S, Richardson DC, Richardson JS.
(2015)
Chapter 7 in Structures of large RNA molecules and their complexes, Ed. Woodson S & Allain F, Methods Enzymol series
558
181-212
doi:
"New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey".
Zhou H, Hintze BJ, Kimsey IJ, Sathyamoorthy B, Yang S, Richardson JS, Al-Hashimi HM.
(2015)
Nucl Acids Res
43
3420-3433
doi: PMC4402545 doi: ??/??/?? (open access)
"New tools provide a second look at HDV ribozyme structure, dynamics and cleavage".
Kapral GJ, Jain S, Noeske J, Doudna JA, Richardson DC, Richardson JS.
(2014)
Nucl Acids Res
42
12833-12846
doi: 10.1093/nar/gku992 (open access)
"Multiscale Conformational Heterogeneity in Staphylococcal Protein A: Possible Determinant of Functional Plasticity".
Deis LN, PembleIV CW, Qi Y, Hagarman A, Richardson DC, Richardson JS, Oas TG.
(2014)
Structure
22
:1467-1477
doi: 10.1016/j.str.2014.08.014 (open access)
"The Statistical Conformation of a Highly Flexible Protein: Small-Angle X-Ray Scattering of S. aureus Protein A".
Capp JoA, Hagarman A, Richardson DC, Oas TG.
(2014)
Structure
22
:1184-1195
doi: 10.1016/j.str.2014.6.011 (open access)
"Automated identification of elemental ions in macromolecular crystal structures".
Echols N, Morshed N, Afonine PV, McCoy AJ, Miller MD, Read RJ, Richardson JS, Terwilliger TC, Adams PD.
(2014)
Acta Cryst
D70
:1104-1114
doi: 10.1107/S1399004714001308
"Biophysical Highlights from 54 Years of Macromolecular Crystallography".
Richardson JS, Richardson DC.
(2014)
Biophysical Journal
106
:510-525
doi: 10.1016/j.bpj.2014.01.001
"Recommendations of the wwPDB NMR Validation Task Force".
Montelione GT, Nilges M, Bax A, Güntert P, Herrmann T, Richardson JS, Schwieters CD, Vranken WF, Vuister GW, Wishart DS, Berman HM, Kleywegt GJ, Markley JL.
(2013)
Structure
21
:1563-1570
doi: 10.1016/j.str.2013.07.021
"Crystallographic model validation: from diagnosis to healing".
Richardson JS, Prisant MG, Richardson DC.
(2013)
Curr Op Struct Biol
23
:707-714
doi: 10.1016/j.sbi.2013.06.004
"The Zen of model anomalies – Correct most of them. Treasure the meaningful valid few. Live serenely with the rest.".
Richardson JS and Richardson DC.
(2013)
In Advancing Methods in Biomolecular Crystallography, ed Read RJ, NATO conference volume from 2012 Erice crystallography school, Springer, (publ April 2013)
pages:1-10
doi: 10.1007/978-94-007-6232-9
"Advances, interactions, and future developments in the CNS, Phenix, and Rosetta structural biology software systems".
Adams PD, Baker D, Brunger AT, Das R, DiMaio F, Read RJ, Richardson JS, Terwilliger TC.
(2013)
Ann. Rev. Biophys.
42
:265-287
doi: 10.1146/annurev-biophys-083012-130253
"Doing molecular biophysics: Finding, naming, and picturing signal within complexity".
Richardson JS and Richardson DC.
(2013)
Ann. Rev. Biophys.
42
:1-28
doi: 10.1146/annurev-biophys-083012-130353
"OSPREY: Protein Design with Ensembles, Flexibility, and Provable Algorithms".
Gainza P, Roberts KE, Georgiev I, Lilien RH, Keedy DA, Chen C-Y, Reza F, Anderson AC, Richardson DC, Richardson JS and Donald BR.
(2013)
Meth Enzymol
523
:87-107
doi: 10.1016/B978-0-12-394292-0.00005-9
"Scientific benchmarks for updating the Rosetta energy function".
Leaver-Fay A, O'Meara MJ, Tyka M, Jacak R, Song Y, Kellogg EH, Thompson J, Davis IW, Pache RA, Lyskov S, Gray JJ, Kortemme T, Richardson JS, Havranek JJ, Snoeyink J, Baker D, Kuhlman B.
(2013)
Meth Enzymol
523
109-143
doi: 10.1016/B978-0-12-394292-0.00006-0
"The Plot" Thickens: More Data, More Dimensions, More Uses".
Richardson JS, Keedy DK, & Richardson DC.
(2013)
Book Chapter:
doi:
"Studying and Polishing the PDB’s Macromolecules".
Richardson JS & Richardson DC.
(2012)
Biopolymers
99(3)
170-182
doi: 10.1002/bip.22108
"The Role of Local Backrub Motions in Evolved and Designed Mutations.".
Keedy DA, Georgiev I, Triplett EB, Donald BR, Richardson DC, & Richardson JS.
(2012)
PLoS Comp Biol
8(8)
.
doi: 10.1371/journal.pcbi.1002629
"Structures of the Bacterial Ribosome in Classical and Hybrid States of tRNA Binding".
Dunkle JA, Wang L, Feldman MB, Pulk A, Chen VB, Kapral GJ, Noeske J, Richardson JS, Blanchard SC, & Doudna Cate JH.
(2011)
Science
332
981-984
doi:
"Alternate States of Proteins Revealed by Detailed Energy Landscape Mapping".
Tyka MD, Keedy DA, André I, DiMaio F, Song Y, Richardson DC, Richardson JS & David Baker D.
(2011)
J Mol Biol
405(2)
607-618
doi: /10.1016/j.jmb.2010.11.008
"Recent developments in phasing and structure refinement for macromolecular crystallography".
Adams PD, Afonine PV, Grosse-Kunstleve RW, Read RJ, Richardson JS, Richardson DC & Terwilliger TC.
(2009)
Current Opinion in Structural Biology
19
:566-572
doi: 10.1016/j.sbi.2009.07.014
"KiNG (Kinemage, Next Generation): A versatile interactive molecular and scientific visualization program".
Chen VB, Davis IW & Richardson DC.
(2009)
Protein Sci
18
:2403-2409
doi: 10.1002/pro.250
"The other 90% of the protein: Assessment beyond the Cαs for CASP8 template-based and high-accuracy models".
Keedy DA, Williams CJ, Headd JJ, Arendall WB, Chen VB, Kapral GJ, Gillespie RA, Block JN, Zemla A, Richardson DC & Richardson JS.
(2009)
Proteins: Struc Func Bioinf
77(Suppl 9)
:29-49
doi: 10.1002/prot.22551
"The Impact of Local Accuracy In Protein and RNA Structures: Validation As an Active Tool".
Richardson JS & Richardson DC.
(2009)
Chapter 15 in Structural Bioinformatics, 2nd Edition
doi: 2009
"Autofix for backward-fit sidechains: using MolProbity and real-space refinement to put misfits in their place".
Headd JJ, Immormino RM, Keedy DA, Emsley P, Richardson DC & Richardson JS.
(2009)
J Struc Func Genomics
10
:83-93
doi: 10.1007/s10969-008-9045-8
"Algorithm for backrub motions in protein design".
Georgiev I, Keedy DA, Richardson JS, Richardson DC & Donald BR.
(2008)
Bioinformatics
24
:i196-i204
doi: 10.1093/bioinformatics/btn169
"RNABC: forward kinematics to reduce all-atom steric clashes in RNA backbone".
Wang X, Kapral GJ, Murray LW, Richardson DC, Richardson JS & Snoeyink J.
(2008)
J Math Biol
56
:253-278
doi: 10.1007/s00285-007-0082
"MolProbity: all-atom contacts and structure validation for proteins and nucleic acids".
Davis IW, Leaver-Fay A, Chen VB, Block JN, Kapral GJ, Wang X, Murray LW, Arendall WB, Snoeyink J, Richardson JS & Richardson DC.
(2007)
Nucleic Acids Res
35
W375-W383
doi: 10.1093/nar/gkm216
"The backrub motion: How protein backbone shrugs when a sidechain dances".
Davis IW, Arendall WB, Richardson DC, & Richardson JS.
(2006)
Structure
14
265-274
doi: 10.1016/j.str.2005.10.007
"The RNA Ontology Consortium: An Open Invitation to the RNA Community".
Leontis NB, Altman R, Berman HM, Brenner SE, Brown J, Engelke D, Harvey SC, Holbrook SR, Jossinet F, Lewis SE, Major F, Mathews DH, Richardson JS, Williamson JR & Westhof E.
(2006)
RNA
12
533-541
doi: 10.1261/rna.2343206
"A test of enhancing model accuracy in high-throughput crystallography".
Arendall WB, Tempel W, Richardson JS, Zhou W, Wang S, Davis IW, Liu Z-J, Rose JP, Carson WM, Luo M, Richardson DC, & Wang B-C..
(2005)
J Struc Func Genomics
6
1-11
doi: 10.1007/s10969-005-3138-4
"MolProbity: structure validation and all-atom contact analysis for nucleic acids and their complexes".
Davis IW, Murray LW, Richardson JS, & Richardson DC..
(2004)
. Nucleic Acids Res
32
W615-619
doi: 10.1093/nar/gkh398
"The Cis Pro Touch-Turn: A Rare Motif Preferred at Functional Sites".
Videau LL, Arendall WB, & Richardson JS..
(2004)
Proteins: Struc Func Bioinf
56
298-309
doi: 10.1002/prot.20101
"Kinetic Role of Helix Caps in Protein Folding is Context-Dependent".
Kapp GT, Richardson JS, & Oas TG..
(2004)
Biochemistry
43
3814-3823
doi: 10.1021/bi035683k
"Structure Validation by Cα Geometry: φ,ψ and Cβ Deviation.".
Lovell SC, Davis IW, Arendall WB, de Bakker PIW, Word JM, Prisant MG, Richardson JS, & Richardson DC.
(2003)
Proteins: Struc Func Genet
50
437-450
doi: 10.1002/prot.10286
"New Tools and Data for Improving Structures, Using All-Atom Contacts.".
Richardson JS, Arendall WB, & Richardson DC.
(2003)
Methods in Enzymology: Macromolecular Crystallography, Part D
374
385-412
doi:
