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Title: qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps

Abstract

Here, proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein–ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor–ligand complexes. In an analysis of the cancer related BRD4 domain, we found that up to 29% of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand–receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multitemperature crystallography could therefore augment the structure-based drug design toolbox.

Authors:
 [1]; ORCiD logo [2];  [3];  [2];  [4];  [5];  [2];  [1];  [1];  [2]; ORCiD logo [6]
+ Show Author Affiliations
  1. Schrodinger, New York, NY (United States)
  2. UCSF, San Francisco, CA (United States)
  3. Stanford Univ., Stanford, CA (United States). SLAC National Accelerator Lab
  4. Stanford Univ., Stanford, CA (United States)
  5. Univ. Paris-Saclay, Palaiseau (France)
  6. UCSF, San Francisco, CA (United States); Stanford Univ., Stanford, CA (United States). SLAC National Accelerator Lab
Publication Date:
Research Org.:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1493576
Grant/Contract Number:  
AC02-76SF00515; NNF15OC0015268; STC-1231306; LFR-17-476732; GM123159; GM124149
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 24; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

van Zundert, Gydo C. P., Hudson, Brandi M., de Oliveira, Saulo H. P., Keedy, Daniel A., Fonseca, Rasmus, Heliou, Amelie, Suresh, Pooja, Borrelli, Kenneth, Day, Tyler, Fraser, James S., and van den Bedem, Henry. qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b01292.
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van Zundert, Gydo C. P., Hudson, Brandi M., de Oliveira, Saulo H. P., Keedy, Daniel A., Fonseca, Rasmus, Heliou, Amelie, Suresh, Pooja, Borrelli, Kenneth, Day, Tyler, Fraser, James S., & van den Bedem, Henry. qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps. United States. https://doi.org/10.1021/acs.jmedchem.8b01292
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van Zundert, Gydo C. P., Hudson, Brandi M., de Oliveira, Saulo H. P., Keedy, Daniel A., Fonseca, Rasmus, Heliou, Amelie, Suresh, Pooja, Borrelli, Kenneth, Day, Tyler, Fraser, James S., and van den Bedem, Henry. Tue . "qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps". United States. https://doi.org/10.1021/acs.jmedchem.8b01292. https://www.osti.gov/servlets/purl/1493576.
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@article{osti_1493576,
title = {qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps},
author = {van Zundert, Gydo C. P. and Hudson, Brandi M. and de Oliveira, Saulo H. P. and Keedy, Daniel A. and Fonseca, Rasmus and Heliou, Amelie and Suresh, Pooja and Borrelli, Kenneth and Day, Tyler and Fraser, James S. and van den Bedem, Henry},
abstractNote = {Here, proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein–ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor–ligand complexes. In an analysis of the cancer related BRD4 domain, we found that up to 29% of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand–receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multitemperature crystallography could therefore augment the structure-based drug design toolbox.},
doi = {10.1021/acs.jmedchem.8b01292},
journal = {Journal of Medicinal Chemistry},
number = 24,
volume = 61,
place = {United States},
year = {2018},
month = {11}
}
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Works referenced in this record:

Protein activity regulation by conformational entropy
journal, July 2012

  • Tzeng, Shiou-Ru; Kalodimos, Charalampos G.
  • Nature, Vol. 488, Issue 7410
  • DOI: 10.1038/nature11271

Entropy in molecular recognition by proteins
journal, June 2017

  • Caro, José A.; Harpole, Kyle W.; Kasinath, Vignesh
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 25
  • DOI: 10.1073/pnas.1621154114

Binding of Small-Molecule Ligands to Proteins: “What You See” Is Not Always “What You Get”
journal, April 2009

Integrative, dynamic structural biology at atomic resolution—it's about time
journal, March 2015

  • van den Bedem, Henry; Fraser, James S.
  • Nature Methods, Vol. 12, Issue 4
  • DOI: 10.1038/nmeth.3324

Structural heterogeneity in protein crystals
journal, September 1986

  • Smith, Janet L.; Hendrickson, Wayne A.; Honzatko, Richard B.
  • Biochemistry, Vol. 25, Issue 18
  • DOI: 10.1021/bi00366a008

Automated electron-density sampling reveals widespread conformational polymorphism in proteins: Electron-density Sampling Detects Hidden Ensembles
journal, May 2010

  • Lang, P. Therese; Ng, Ho-Leung; Fraser, James S.
  • Protein Science, Vol. 19, Issue 7
  • DOI: 10.1002/pro.423

Modelling dynamics in protein crystal structures by ensemble refinement
journal, December 2012

Evidence for dynamics in proteins as a mechanism for ligand dissociation
journal, January 2012

  • Carroll, Mary J.; Mauldin, Randall V.; Gromova, Anna V.
  • Nature Chemical Biology, Vol. 8, Issue 3
  • DOI: 10.1038/nchembio.769

Direct Detection of Structurally Resolved Dynamics in a Multiconformation Receptor−Ligand Complex
journal, April 2011

  • Carroll, Mary J.; Gromova, Anna V.; Miller, Keith R.
  • Journal of the American Chemical Society, Vol. 133, Issue 16
  • DOI: 10.1021/ja2005253

Ligand-Based Prediction of Active Conformation by 3D-QSAR Flexibility Descriptors and Their Application in 3+3D-QSAR Models
journal, May 2005

  • Martinek, Tamás A.; Dervarics, Máté; Tóth, Géza
  • Journal of Medicinal Chemistry, Vol. 48, Issue 9
  • DOI: 10.1021/jm049157i

Tracing Binding Modes in Hit-to-Lead Optimization: Chameleon-Like Poses of Aspartic Protease Inhibitors
journal, January 2015

  • Kuhnert, Maren; Köster, Helene; Bartholomäus, Ruben
  • Angewandte Chemie International Edition, Vol. 54, Issue 9
  • DOI: 10.1002/anie.201411206

Ligand deconstruction: Why some fragment binding positions are conserved and others are not
journal, April 2015

  • Kozakov, Dima; Hall, David R.; Jehle, Stefan
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 20
  • DOI: 10.1073/pnas.1501567112

Discovery of potent and selective CDK8 inhibitors through FBDD approach
journal, September 2017

  • Han, Xingchun; Jiang, Min; Zhou, Chengang
  • Bioorganic & Medicinal Chemistry Letters, Vol. 27, Issue 18
  • DOI: 10.1016/j.bmcl.2017.07.080

Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors
journal, August 2014

  • Casale, Elena; Amboldi, Nadia; Brasca, Maria Gabriella
  • Bioorganic & Medicinal Chemistry, Vol. 22, Issue 15
  • DOI: 10.1016/j.bmc.2014.05.056

One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening
journal, June 2009

  • Mpamhanga, Chidochangu P.; Spinks, Daniel; Tulloch, Lindsay B.
  • Journal of Medicinal Chemistry, Vol. 52, Issue 14
  • DOI: 10.1021/jm900414x

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA 2 ) Discovered through X-ray Fragment Screening
journal, May 2016

  • Woolford, Alison J. -A.; Pero, Joseph E.; Aravapalli, Sridhar
  • Journal of Medicinal Chemistry, Vol. 59, Issue 11
  • DOI: 10.1021/acs.jmedchem.6b00212

Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models
journal, July 2015

  • Plattner, Nuria; Noé, Frank
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms8653

Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
journal, December 2017

  • Porter, Nicholas J.; Mahendran, Adaickapillai; Breslow, Ronald
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 51
  • DOI: 10.1073/pnas.1718823114

Inhibitors of the tyrosine kinase EphB4. Part 2: Structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines
journal, November 2008

  • Bardelle, Catherine; Coleman, Tanya; Cross, Darren
  • Bioorganic & Medicinal Chemistry Letters, Vol. 18, Issue 21
  • DOI: 10.1016/j.bmcl.2008.09.087

Drug design from the cryptic inhibitor envelope
journal, February 2016

  • Lee, Chul-Jin; Liang, Xiaofei; Wu, Qinglin
  • Nature Communications, Vol. 7, Issue 1
  • DOI: 10.1038/ncomms10638

Automated identification of functional dynamic contact networks from X-ray crystallography
journal, August 2013

  • van den Bedem, Henry; Bhabha, Gira; Yang, Kun
  • Nature Methods, Vol. 10, Issue 9
  • DOI: 10.1038/nmeth.2592

Modeling discrete heterogeneity in X-ray diffraction data by fitting multi-conformers
journal, September 2009

  • van den Bedem, Henry; Dhanik, Ankur; Latombe, Jean-Claude
  • Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10
  • DOI: 10.1107/S0907444909030613

Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit
journal, October 2015

Ensemble Refinement of Protein Crystal Structures: Validation and Application
journal, September 2007

A rapid method for positioning small flexible molecules, nucleic acids, and large protein fragments in experimental electron density maps
journal, September 1999

X-LIGAND : an application for the automated addition of flexible ligands into electron density
journal, April 2001

  • Oldfield, T. J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 57, Issue 5
  • DOI: 10.1107/S0907444901003894

Modelling bound ligands in protein crystal structures
journal, November 2004

  • Zwart, P. H.; Langer, G. G.; Lamzin, V. S.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
  • DOI: 10.1107/S0907444904012995

Automated crystallographic ligand building using the medial axis transform of an electron-density isosurface
journal, September 2005

  • Aishima, Jun; Russel, Daniel S.; Guibas, Leonidas J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 61, Issue 10
  • DOI: 10.1107/S0907444905023152

Automated ligand fitting by core-fragment fitting and extension into density
journal, July 2006

  • Terwilliger, Thomas C.; Klei, Herbert; Adams, Paul D.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8
  • DOI: 10.1107/S0907444906017161

Assessment of automatic ligand building in ARP / wARP
journal, December 2006

  • Evrard, Guillaume X.; Langer, Gerrit G.; Perrakis, Anastassis
  • Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 1
  • DOI: 10.1107/S0907444906023389

Improved ligand geometries in crystallographic refinement using AFITT in PHENIX
journal, August 2016

  • Janowski, Pawel A.; Moriarty, Nigel W.; Kelley, Brian P.
  • Acta Crystallographica Section D Structural Biology, Vol. 72, Issue 9
  • DOI: 10.1107/S2059798316012225

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Correlation between occupancy and temperature factors of solvent molecules in crystal structures of proteins
journal, January 1989

  • Bhat, T. N.
  • Acta Crystallographica Section A Foundations of Crystallography, Vol. 45, Issue 1
  • DOI: 10.1107/S0108767388008967

Correlation between occupancy and B factor of water molecules in protein crystal structures
journal, December 1999

Estimating Electron Density Support for Individual Atoms and Molecular Fragments in X-ray Structures
journal, October 2017

  • Meyder, Agnes; Nittinger, Eva; Lange, Gudrun
  • Journal of Chemical Information and Modeling, Vol. 57, Issue 10
  • DOI: 10.1021/acs.jcim.7b00391

The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer
journal, July 2012

  • Lewis, Richard T.; Bode, Christiane M.; Choquette, Deborah M.
  • Journal of Medicinal Chemistry, Vol. 55, Issue 14
  • DOI: 10.1021/jm3005866

Conformational Analysis of Drug-Like Molecules Bound to Proteins:  An Extensive Study of Ligand Reorganization upon Binding
journal, May 2004

  • Perola, Emanuele; Charifson, Paul S.
  • Journal of Medicinal Chemistry, Vol. 47, Issue 10
  • DOI: 10.1021/jm030563w

Motifs for molecular recognition exploiting hydrophobic enclosure in protein–ligand binding
journal, January 2007

  • Young, Tom; Abel, Robert; Kim, Byungchan
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 3
  • DOI: 10.1073/pnas.0610202104

Applying thermodynamic profiling in lead finding and optimization
journal, January 2015

  • Klebe, Gerhard
  • Nature Reviews Drug Discovery, Vol. 14, Issue 2
  • DOI: 10.1038/nrd4486

How good is fluorine as a hydrogen bond acceptor?
journal, September 1996

A Real-World Perspective on Molecular Design: Miniperspective
journal, February 2016

Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family
journal, March 2012

Epigenetic protein families: a new frontier for drug discovery
journal, April 2012

  • Arrowsmith, Cheryl H.; Bountra, Chas; Fish, Paul V.
  • Nature Reviews Drug Discovery, Vol. 11, Issue 5
  • DOI: 10.1038/nrd3674

A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation-π Interaction
journal, May 2014

  • Rooney, Timothy P. C.; Filippakopoulos, Panagis; Fedorov, Oleg
  • Angewandte Chemie International Edition, Vol. 53, Issue 24
  • DOI: 10.1002/anie.201402750

Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities
journal, December 2015

  • Chekler, Eugene L. Piatnitski; Pellegrino, Jessica A.; Lanz, Thomas A.
  • Chemistry & Biology, Vol. 22, Issue 12
  • DOI: 10.1016/j.chembiol.2015.10.013

Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains
journal, June 2014

  • Hay, Duncan A.; Fedorov, Oleg; Martin, Sarah
  • Journal of the American Chemical Society, Vol. 136, Issue 26
  • DOI: 10.1021/ja412434f

Naphthyridines as Novel BET Family Bromodomain Inhibitors
journal, September 2013

Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A)
journal, April 2012

  • Seal, Jonathan; Lamotte, Yann; Donche, Frédéric
  • Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 8
  • DOI: 10.1016/j.bmcl.2012.02.041

Accessing protein conformational ensembles using room-temperature X-ray crystallography
journal, September 2011

  • Fraser, J. S.; van den Bedem, H.; Samelson, A. J.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 39
  • DOI: 10.1073/pnas.1111325108

One Crystal, Two Temperatures: Cryocooling Penalties Alter Ligand Binding to Transient Protein Sites
journal, June 2015

  • Fischer, Marcus; Shoichet, Brian K.; Fraser, James S.
  • ChemBioChem, Vol. 16, Issue 11
  • DOI: 10.1002/cbic.201500196

Essential considerations for using protein–ligand structures in drug discovery
journal, December 2012

Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop
journal, April 2016

The Protein Data Bank
journal, January 2000

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins
journal, December 2015

  • Harder, Edward; Damm, Wolfgang; Maple, Jon
  • Journal of Chemical Theory and Computation, Vol. 12, Issue 1
  • DOI: 10.1021/acs.jctc.5b00864

ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers
journal, April 2010

  • Watts, K. Shawn; Dalal, Pranav; Murphy, Robert B.
  • Journal of Chemical Information and Modeling, Vol. 50, Issue 4
  • DOI: 10.1021/ci100015j

Macrocycle Conformational Sampling with MacroModel
journal, September 2014

  • Watts, K. Shawn; Dalal, Pranav; Tebben, Andrew J.
  • Journal of Chemical Information and Modeling, Vol. 54, Issue 10
  • DOI: 10.1021/ci5001696

Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database
journal, March 2010

  • Hawkins, Paul C. D.; Skillman, A. Geoffrey; Warren, Gregory L.
  • Journal of Chemical Information and Modeling, Vol. 50, Issue 4
  • DOI: 10.1021/ci100031x

LowModeMD—Implicit Low-Mode Velocity Filtering Applied to Conformational Search of Macrocycles and Protein Loops
journal, April 2010

  • Labute, Paul
  • Journal of Chemical Information and Modeling, Vol. 50, Issue 5
  • DOI: 10.1021/ci900508k

Freely Available Conformer Generation Methods: How Good Are They?
journal, April 2012

  • Ebejer, Jean-Paul; Morris, Garrett M.; Deane, Charlotte M.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 5
  • DOI: 10.1021/ci2004658

A multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density
journal, April 2017

  • Pearce, Nicholas M.; Krojer, Tobias; Bradley, Anthony R.
  • Nature Communications, Vol. 8, Issue 1
  • DOI: 10.1038/ncomms15123

Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery
journal, June 2016

Room-temperature macromolecular serial crystallography using synchrotron radiation
journal, May 2014

Time-resolved serial crystallography captures high-resolution intermediates of photoactive yellow protein
journal, December 2014

Structural enzymology using X-ray free electron lasers
journal, December 2016

  • Kupitz, Christopher; Olmos, Jose L.; Holl, Mark
  • Structural Dynamics, Vol. 4, Issue 4
  • DOI: 10.1063/1.4972069

Enzyme intermediates captured “on the fly” by mix-and-inject serial crystallography
journal, May 2018

HIV-1 Protease Inhibitors:  Enthalpic versus Entropic Optimization of the Binding Affinity †
journal, March 2000

  • Velazquez-Campoy, Adrian; Todd, Matthew J.; Freire, Ernesto
  • Biochemistry, Vol. 39, Issue 9
  • DOI: 10.1021/bi992399d

Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design
journal, May 2013

Rational Approaches to Improving Selectivity in Drug Design
journal, January 2012

  • Huggins, David J.; Sherman, Woody; Tidor, Bruce
  • Journal of Medicinal Chemistry, Vol. 55, Issue 4
  • DOI: 10.1021/jm2010332

A dynamic Asp–Arg interaction is essential for catalysis in microsomal prostaglandin E 2 synthase
journal, January 2016

  • Brock, Joseph S.; Hamberg, Mats; Balagunaseelan, Navisraj
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 4
  • DOI: 10.1073/pnas.1522891113

Automated main-chain model building by template matching and iterative fragment extension
journal, December 2002

  • Terwilliger, Thomas C.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 59, Issue 1
  • DOI: 10.1107/S0907444902018036

Algorithm for cardinality-constrained quadratic optimization
journal, November 2007

  • Bertsimas, Dimitris; Shioda, Romy
  • Computational Optimization and Applications, Vol. 43, Issue 1
  • DOI: 10.1007/s10589-007-9126-9

Subset selection by Mallows’ Cp: A mixed integer programming approach
journal, January 2015

F lex S:  A Method for Fast Flexible Ligand Superposition
journal, November 1998

  • Lemmen, Christian; Lengauer, Thomas; Klebe, Gerhard
  • Journal of Medicinal Chemistry, Vol. 41, Issue 23
  • DOI: 10.1021/jm981037l

Protein structural ensembles are revealed by redefining X-ray electron density noise
journal, December 2013

  • Lang, P. T.; Holton, J. M.; Fraser, J. S.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 1
  • DOI: 10.1073/pnas.1302823110

mmLib Python toolkit for manipulating annotated structural models of biological macromolecules
journal, January 2004

MemBrain: Improving the Accuracy of Predicting Transmembrane Helices
journal, June 2008

Optimized Torsion-Angle Normal Modes Reproduce Conformational Changes More Accurately Than Cartesian Modes
journal, December 2011

  • Bray, Jenelle K.; Weiss, Dahlia R.; Levitt, Michael
  • Biophysical Journal, Vol. 101, Issue 12
  • DOI: 10.1016/j.bpj.2011.10.054

Confidence intervals for fitting of atomic models into low-resolution densities
journal, June 2009

  • Volkmann, Niels
  • Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 7
  • DOI: 10.1107/S0907444909012876

Defining the limits and reliability of rigid-body fitting in cryo-EM maps using multi-scale image pyramids
journal, August 2016

Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences
journal, July 2013

  • Bochevarov, Art D.; Harder, Edward; Hughes, Thomas F.
  • International Journal of Quantum Chemistry, Vol. 113, Issue 18
  • DOI: 10.1002/qua.24481

Density Functionals with Broad Applicability in Chemistry
journal, February 2008

  • Zhao, Yan; Truhlar, Donald G.
  • Accounts of Chemical Research, Vol. 41, Issue 2
  • DOI: 10.1021/ar700111a
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