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Title: Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation

Abstract

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampledmore » molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.« less

Authors:
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1566978
Alternate Identifier(s):
OSTI ID: 1565964
Grant/Contract Number:  
AC05-00OR22725; ERKP300
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 41; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Shrestha, Utsab R., Juneja, Puneet, Borreguero Calvo, Jose M., Zhang, Qiu, Pingali, Sai Venkatesh, Cheng, Xiaolin, Urban, Volker S., Smith, Jeremy C., O'Neill, Hugh, and Petridis, Loukas. Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation. United States: N. p., 2019. Web. doi:10.1073/pnas.1907251116.
Shrestha, Utsab R., Juneja, Puneet, Borreguero Calvo, Jose M., Zhang, Qiu, Pingali, Sai Venkatesh, Cheng, Xiaolin, Urban, Volker S., Smith, Jeremy C., O'Neill, Hugh, & Petridis, Loukas. Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation. United States. doi:10.1073/pnas.1907251116.
Shrestha, Utsab R., Juneja, Puneet, Borreguero Calvo, Jose M., Zhang, Qiu, Pingali, Sai Venkatesh, Cheng, Xiaolin, Urban, Volker S., Smith, Jeremy C., O'Neill, Hugh, and Petridis, Loukas. Mon . "Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation". United States. doi:10.1073/pnas.1907251116.
@article{osti_1566978,
title = {Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation},
author = {Shrestha, Utsab R. and Juneja, Puneet and Borreguero Calvo, Jose M. and Zhang, Qiu and Pingali, Sai Venkatesh and Cheng, Xiaolin and Urban, Volker S. and Smith, Jeremy C. and O'Neill, Hugh and Petridis, Loukas},
abstractNote = {Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.},
doi = {10.1073/pnas.1907251116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 41,
volume = 116,
place = {United States},
year = {2019},
month = {9}
}

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Works referenced in this record:

Hydration and interactions in protein solutions containing concentrated electrolytes studied by small-angle scattering
journal, January 2012

  • Zhang, F.; Roosen-Runge, F.; Skoda, M. W. A.
  • Physical Chemistry Chemical Physics, Vol. 14, Issue 7
  • DOI: 10.1039/c2cp23460b

Towards the Structural Characterization of Intrinsically Disordered Proteins by SAXS and MD Simulation
journal, January 2011


Juxtanodin is an intrinsically disordered F-actin-binding protein
journal, November 2012

  • Ruskamo, Salla; Chukhlieb, Maryna; Vahokoski, Juha
  • Scientific Reports, Vol. 2, Issue 1
  • DOI: 10.1038/srep00899

Is the first hydration shell of lysozyme of higher density than bulk water?
journal, April 2002

  • Merzel, F.; Smith, J. C.
  • Proceedings of the National Academy of Sciences, Vol. 99, Issue 8
  • DOI: 10.1073/pnas.082335099

Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water
journal, October 2017

  • Riback, Joshua A.; Bowman, Micayla A.; Zmyslowski, Adam M.
  • Science, Vol. 358, Issue 6360
  • DOI: 10.1126/science.aan5774

SHIFTX2: significantly improved protein chemical shift prediction
journal, March 2011

  • Han, Beomsoo; Liu, Yifeng; Ginzinger, Simon W.
  • Journal of Biomolecular NMR, Vol. 50, Issue 1
  • DOI: 10.1007/s10858-011-9478-4

Effects of Macromolecular Crowding on an Intrinsically Disordered Protein Characterized by Small-Angle Neutron Scattering with Contrast Matching
journal, February 2011

  • Johansen, Daniel; Jeffries, Cy M. J.; Hammouda, Boualem
  • Biophysical Journal, Vol. 100, Issue 4
  • DOI: 10.1016/j.bpj.2011.01.020

Transient tertiary structures in tau, an intrinsically disordered protein
journal, November 2013


Bayesian ensemble refinement by replica simulations and reweighting
journal, December 2015

  • Hummer, Gerhard; Köfinger, Jürgen
  • The Journal of Chemical Physics, Vol. 143, Issue 24
  • DOI: 10.1063/1.4937786

I-TASSER: a unified platform for automated protein structure and function prediction
journal, March 2010

  • Roy, Ambrish; Kucukural, Alper; Zhang, Yang
  • Nature Protocols, Vol. 5, Issue 4
  • DOI: 10.1038/nprot.2010.5

Minimal Effects of Macromolecular Crowding on an Intrinsically Disordered Protein: A Small-Angle Neutron Scattering Study
journal, February 2014


The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases
journal, April 2017


Intrinsically disordered proteins in cellular signalling and regulation
journal, December 2014

  • Wright, Peter E.; Dyson, H. Jane
  • Nature Reviews Molecular Cell Biology, Vol. 16, Issue 1
  • DOI: 10.1038/nrm3920

How accurate are polymer models in the analysis of Förster resonance energy transfer experiments on proteins?
journal, March 2009

  • O’Brien, Edward P.; Morrison, Greg; Brooks, Bernard R.
  • The Journal of Chemical Physics, Vol. 130, Issue 12
  • DOI: 10.1063/1.3082151

Protein Intrinsic Disorder and Human Papillomaviruses:  Increased Amount of Disorder in E6 and E7 Oncoproteins from High Risk HPVs
journal, August 2006

  • Uversky, Vladimir N.; Roman, Ann; Oldfield, Christopher J.
  • Journal of Proteome Research, Vol. 5, Issue 8
  • DOI: 10.1021/pr0602388

Computational and theoretical advances in studies of intrinsically disordered proteins
journal, February 2017


GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
journal, September 2015


Protein hydration in solution: Experimental observation by x-ray and neutron scattering
journal, March 1998

  • Svergun, D. I.; Richard, S.; Koch, M. H. J.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 5
  • DOI: 10.1073/pnas.95.5.2267

Single-Molecule FRET Spectroscopy and the Polymer Physics of Unfolded and Intrinsically Disordered Proteins
journal, July 2016


Protein Structure and Hydration Probed by SANS and Osmotic Stress
journal, April 2008


Charge interactions can dominate the dimensions of intrinsically disordered proteins
journal, July 2010

  • Muller-Spath, S.; Soranno, A.; Hirschfeld, V.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 33
  • DOI: 10.1073/pnas.1001743107

Comment on “Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water”
journal, August 2018


Inferential Structure Determination
journal, July 2005


Decoupling of size and shape fluctuations in heteropolymeric sequences reconciles discrepancies in SAXS vs. FRET measurements
journal, July 2017

  • Fuertes, Gustavo; Banterle, Niccolò; Ruff, Kiersten M.
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 31
  • DOI: 10.1073/pnas.1704692114

Validation of macromolecular flexibility in solution by small-angle X-ray scattering (SAXS)
journal, May 2012


Validating Solution Ensembles from Molecular Dynamics Simulation by Wide-Angle X-ray Scattering Data
journal, July 2014


The amyloid state and its association with protein misfolding diseases
journal, May 2014

  • Knowles, Tuomas P. J.; Vendruscolo, Michele; Dobson, Christopher M.
  • Nature Reviews Molecular Cell Biology, Vol. 15, Issue 6
  • DOI: 10.1038/nrm3810

Note: On the universality of proximal radial distribution functions of proteins
journal, March 2011

  • Lin, Bin; Pettitt, B. Montgomery
  • The Journal of Chemical Physics, Vol. 134, Issue 10
  • DOI: 10.1063/1.3565035

Replica Exchange with Solute Scaling: A More Efficient Version of Replica Exchange with Solute Tempering (REST2)
journal, August 2011

  • Wang, Lingle; Friesner, Richard A.; Berne, B. J.
  • The Journal of Physical Chemistry B, Vol. 115, Issue 30
  • DOI: 10.1021/jp204407d

Intrinsically disordered proteins drive membrane curvature
journal, July 2015

  • Busch, David J.; Houser, Justin R.; Hayden, Carl C.
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms8875

A transient α-helical molecular recognition element in the disordered N-terminus of the Sgs1 helicase is critical for chromosome stability and binding of Top3/Rmi1
journal, September 2013

  • Kennedy, Jessica A.; Daughdrill, Gary W.; Schmidt, Kristina H.
  • Nucleic Acids Research, Vol. 41, Issue 22
  • DOI: 10.1093/nar/gkt817

GROMACS: A message-passing parallel molecular dynamics implementation
journal, September 1995

  • Berendsen, H. J. C.; van der Spoel, D.; van Drunen, R.
  • Computer Physics Communications, Vol. 91, Issue 1-3
  • DOI: 10.1016/0010-4655(95)00042-E

Structural Characterization of the Natively Unfolded N-Terminal Domain of Human c-Src Kinase: Insights into the Role of Phosphorylation of the Unique Domain
journal, August 2009

  • Pérez, Yolanda; Gairí, Margarida; Pons, Miquel
  • Journal of Molecular Biology, Vol. 391, Issue 1
  • DOI: 10.1016/j.jmb.2009.06.018

Response to Comment on “Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water”
journal, August 2018

  • Riback, Joshua A.; Bowman, Micayla A.; Zmyslowski, Adam
  • Science, Vol. 361, Issue 6405
  • DOI: 10.1126/science.aar7949

Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems
journal, June 1993

  • Darden, Tom; York, Darrin; Pedersen, Lee
  • The Journal of Chemical Physics, Vol. 98, Issue 12
  • DOI: 10.1063/1.464397

Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins
journal, November 2018

  • Kim, Do-Hyoung; Han, Kyou-Hoon
  • International Journal of Molecular Sciences, Vol. 19, Issue 11
  • DOI: 10.3390/ijms19113614

Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain
journal, April 2008

  • Wells, M.; Tidow, H.; Rutherford, T. J.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 15
  • DOI: 10.1073/pnas.0801353105

Interpreting solution X-ray scattering data using molecular simulations
journal, April 2018


Random-coil behavior and the dimensions of chemically unfolded proteins
journal, August 2004

  • Kohn, J. E.; Millett, I. S.; Jacob, J.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 34
  • DOI: 10.1073/pnas.0403643101

Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features
journal, December 1983


PKA phosphorylation of Src mediates Rap1 activation in NGF and cAMP signaling in PC12 cells
journal, December 2004


Combining Experiments and Simulations Using the Maximum Entropy Principle
journal, February 2014

  • Boomsma, Wouter; Ferkinghoff-Borg, Jesper; Lindorff-Larsen, Kresten
  • PLoS Computational Biology, Vol. 10, Issue 2
  • DOI: 10.1371/journal.pcbi.1003406

Intrinsically disordered proteins from A to Z
journal, August 2011


Polymorphic transitions in single crystals: A new molecular dynamics method
journal, December 1981

  • Parrinello, M.; Rahman, A.
  • Journal of Applied Physics, Vol. 52, Issue 12
  • DOI: 10.1063/1.328693

Water hydrogen bond analysis on hydrophilic and hydrophobic biomolecule sites
journal, January 2008

  • Russo, Daniela; Ollivier, Jacques; Teixeira, José
  • Physical Chemistry Chemical Physics, Vol. 10, Issue 32
  • DOI: 10.1039/b807551b

Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment
journal, June 2015

  • Henriques, João; Cragnell, Carolina; Skepö, Marie
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 7
  • DOI: 10.1021/ct501178z

A general purpose model for the condensed phases of water: TIP4P/2005
journal, December 2005

  • Abascal, J. L. F.; Vega, C.
  • The Journal of Chemical Physics, Vol. 123, Issue 23
  • DOI: 10.1063/1.2121687

A phosphorylation-motif for tuneable helix stabilisation in intrinsically disordered proteins – Lessons from the sodium proton exchanger 1 (NHE1)
journal, September 2017


Presence and utility of intrinsically disordered regions in kinases
journal, January 2014

  • Kathiriya, Jaymin J.; Pathak, Ravi Ramesh; Clayman, Eric
  • Mol. BioSyst., Vol. 10, Issue 11
  • DOI: 10.1039/C4MB00224E

Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case
journal, January 2016


Small-Angle X-ray Scattering Reveals an Extended Organization for the Autoinhibitory Resting State of the p47 phox Modular Protein
journal, June 2006

  • Durand, Dominique; Cannella, Dominique; Dubosclard, Virginie
  • Biochemistry, Vol. 45, Issue 23
  • DOI: 10.1021/bi060274k

Structural analysis of intrinsically disordered proteins by small-angle X-ray scattering
journal, January 2012

  • Bernadó, Pau; Svergun, Dmitri I.
  • Mol. BioSyst., Vol. 8, Issue 1
  • DOI: 10.1039/c1mb05275f

Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment
journal, September 2016

  • Mollica, Luca; Bessa, Luiza M.; Hanoulle, Xavier
  • Frontiers in Molecular Biosciences, Vol. 3
  • DOI: 10.3389/fmolb.2016.00052

Approaches to altering particle distributions in cryo-electron microscopy sample preparation
journal, May 2018

  • Drulyte, Ieva; Johnson, Rachel M.; Hesketh, Emma L.
  • Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 6
  • DOI: 10.1107/S2059798318006496

Temporary secondary structures in tau, an intrinsically disordered protein
journal, June 2012


Natively unfolded proteins: A point where biology waits for physics
journal, April 2002


Water Dispersion Interactions Strongly Influence Simulated Structural Properties of Disordered Protein States
journal, April 2015

  • Piana, Stefano; Donchev, Alexander G.; Robustelli, Paul
  • The Journal of Physical Chemistry B, Vol. 119, Issue 16
  • DOI: 10.1021/jp508971m

Local Structure and Dynamics of Hydration Water in Intrinsically Disordered Proteins
journal, April 2015

  • Rani, Pooja; Biswas, Parbati
  • The Journal of Physical Chemistry B, Vol. 119, Issue 34
  • DOI: 10.1021/jp511961c

The Role of Src in Solid Tumors
journal, July 2009


Role of p34cdc2-mediated phosphorylations in two-step activation of pp60c-src during mitosis.
journal, August 1992

  • Shenoy, S.; Chackalaparampil, I.; Bagrodia, S.
  • Proceedings of the National Academy of Sciences, Vol. 89, Issue 15
  • DOI: 10.1073/pnas.89.15.7237

Bayesian refinement of protein structures and ensembles against SAXS data using molecular dynamics
journal, October 2017


Using chemical shifts to generate structural ensembles for intrinsically disordered proteins with converged distributions of secondary structure
journal, January 2015


Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues
journal, July 2013

  • Das, R. K.; Pappu, R. V.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 33
  • DOI: 10.1073/pnas.1304749110

Mantid—Data analysis and visualization package for neutron scattering and μ SR experiments
journal, November 2014

  • Arnold, O.; Bilheux, J. C.; Borreguero, J. M.
  • Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, Vol. 764
  • DOI: 10.1016/j.nima.2014.07.029

Why are ?natively unfolded? proteins unstructured under physiologic conditions?
journal, January 2000


Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding
journal, July 2015

  • Arai, Munehito; Sugase, Kenji; Dyson, H. Jane
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 31
  • DOI: 10.1073/pnas.1512799112

Intrinsically Disordered Energy Landscapes
journal, May 2015

  • Chebaro, Yassmine; Ballard, Andrew J.; Chakraborty, Debayan
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep10386

Improved Peptide and Protein Torsional Energetics with the OPLS-AA Force Field
journal, June 2015

  • Robertson, Michael J.; Tirado-Rives, Julian; Jorgensen, William L.
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 7
  • DOI: 10.1021/acs.jctc.5b00356

Intrinsically disordered  -subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure
journal, January 2008

  • Song, J.; Guo, L. -W.; Muradov, H.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 5
  • DOI: 10.1073/pnas.0709558105

ATSAS 2.8 : a comprehensive data analysis suite for small-angle scattering from macromolecular solutions
journal, June 2017

  • Franke, D.; Petoukhov, M. V.; Konarev, P. V.
  • Journal of Applied Crystallography, Vol. 50, Issue 4
  • DOI: 10.1107/S1600576717007786

GROMACS: Fast, flexible, and free
journal, January 2005

  • Van Der Spoel, David; Lindahl, Erik; Hess, Berk
  • Journal of Computational Chemistry, Vol. 26, Issue 16
  • DOI: 10.1002/jcc.20291

Interpreting Protein Structural Dynamics from NMR Chemical Shifts
journal, March 2012

  • Robustelli, Paul; Stafford, Kate A.; Palmer, Arthur G.
  • Journal of the American Chemical Society, Vol. 134, Issue 14
  • DOI: 10.1021/ja300265w

Computer Simulations of Intrinsically Disordered Proteins
journal, May 2017


GROMACS 3.0: a package for molecular simulation and trajectory analysis
journal, August 2001

  • Lindahl, Erik; Hess, Berk; van der Spoel, David
  • Journal of Molecular Modeling, Vol. 7, Issue 8
  • DOI: 10.1007/s008940100045

Structural Characterization of Flexible Proteins Using Small-Angle X-ray Scattering
journal, May 2007

  • Bernadó, Pau; Mylonas, Efstratios; Petoukhov, Maxim V.
  • Journal of the American Chemical Society, Vol. 129, Issue 17
  • DOI: 10.1021/ja069124n

On the Calculation of SAXS Profiles of Folded and Intrinsically Disordered Proteins from Computer Simulations
journal, August 2018

  • Henriques, João; Arleth, Lise; Lindorff-Larsen, Kresten
  • Journal of Molecular Biology, Vol. 430, Issue 16
  • DOI: 10.1016/j.jmb.2018.03.002

GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit
journal, February 2013


Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy
journal, September 2012

  • Hofmann, H.; Soranno, A.; Borgia, A.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 40
  • DOI: 10.1073/pnas.1207719109

Hydration shell of the TS-Kappa protein: Higher density than bulk water
journal, December 2015

  • Barbosa, Rafael de C.; Barbosa, Marcia C.
  • Physica A: Statistical Mechanics and its Applications, Vol. 439
  • DOI: 10.1016/j.physa.2015.07.026

Effects of Acids, Bases, and Heteroatoms on Proximal Radial Distribution Functions for Proteins
journal, March 2015

  • Nguyen, Bao Linh; Pettitt, B. Montgomery
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 4
  • DOI: 10.1021/ct501116v

Classification of Intrinsically Disordered Regions and Proteins
journal, December 2013

  • van der Lee, Robin; Buljan, Marija; Lang, Benjamin
  • Chemical Reviews, Vol. 114, Issue 13
  • DOI: 10.1021/cr400525m

Balanced Protein–Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association
journal, October 2014

  • Best, Robert B.; Zheng, Wenwei; Mittal, Jeetain
  • Journal of Chemical Theory and Computation, Vol. 10, Issue 11
  • DOI: 10.1021/ct500569b


journal, February 2012

  • Receveur-Brechot, Veronique; Durand, Dominique
  • Current Protein & Peptide Science, Vol. 13, Issue 1
  • DOI: 10.2174/138920312799277901

The extended Q -range small-angle neutron scattering diffractometer at the SNS
journal, July 2010


CHARMM36m: an improved force field for folded and intrinsically disordered proteins
journal, November 2016

  • Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz
  • Nature Methods, Vol. 14, Issue 1
  • DOI: 10.1038/nmeth.4067

Simulation Analysis of the Temperature Dependence of Lignin Structure and Dynamics
journal, December 2011

  • Petridis, Loukas; Schulz, Roland; Smith, Jeremy C.
  • Journal of the American Chemical Society, Vol. 133, Issue 50
  • DOI: 10.1021/ja206839u

Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth
journal, May 2015

  • Nors Pedersen, Martin; Foderà, Vito; Horvath, Istvan
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep10422

PLUMED: A portable plugin for free-energy calculations with molecular dynamics
journal, October 2009

  • Bonomi, Massimiliano; Branduardi, Davide; Bussi, Giovanni
  • Computer Physics Communications, Vol. 180, Issue 10
  • DOI: 10.1016/j.cpc.2009.05.011

Small-angle scattering and 3D structure interpretation
journal, October 2016


Statistical Mechanics of the Denatured State of a Protein Using Replica-Averaged Metadynamics
journal, June 2014

  • Camilloni, Carlo; Vendruscolo, Michele
  • Journal of the American Chemical Society, Vol. 136, Issue 25
  • DOI: 10.1021/ja5027584

Introducing Protein Intrinsic Disorder
journal, December 2013

  • Habchi, Johnny; Tompa, Peter; Longhi, Sonia
  • Chemical Reviews, Vol. 114, Issue 13
  • DOI: 10.1021/cr400514h

Multidomain assembled states of Hck tyrosine kinase in solution
journal, August 2010

  • Yang, S.; Blachowicz, L.; Makowski, L.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 36
  • DOI: 10.1073/pnas.1004569107

Intrinsically Disordered Protein Exhibits Both Compaction and Expansion under Macromolecular Crowding
journal, March 2018


Protein Simulations with an Optimized Water Model: Cooperative Helix Formation and Temperature-Induced Unfolded State Collapse
journal, November 2010

  • Best, Robert B.; Mittal, Jeetain
  • The Journal of Physical Chemistry B, Vol. 114, Issue 46
  • DOI: 10.1021/jp108618d

Intrinsically Disordered Proteins in Human Diseases: Introducing the D 2 Concept
journal, June 2008


The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments
journal, October 2015

  • Granata, Daniele; Baftizadeh, Fahimeh; Habchi, Johnny
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep15449

Developing a molecular dynamics force field for both folded and disordered protein states
journal, May 2018

  • Robustelli, Paul; Piana, Stefano; Shaw, David E.
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 21
  • DOI: 10.1073/pnas.1800690115

Hamiltonian replica exchange in GROMACS: a flexible implementation
journal, August 2013


Biophysical experiments and biomolecular simulations: A perfect match?
journal, July 2018


Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment
journal, October 2015

  • Rauscher, Sarah; Gapsys, Vytautas; Gajda, Michal J.
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 11
  • DOI: 10.1021/acs.jctc.5b00736

Lipid binding by the Unique and SH3 domains of c-Src suggests a new regulatory mechanism
journal, February 2013

  • Pérez, Yolanda; Maffei, Mariano; Igea, Ana
  • Scientific Reports, Vol. 3, Issue 1
  • DOI: 10.1038/srep01295

Sassena — X-ray and neutron scattering calculated from molecular dynamics trajectories using massively parallel computers
journal, July 2012


Simultaneous quantification of protein order and disorder
journal, March 2017

  • Sormanni, Pietro; Piovesan, Damiano; Heller, Gabriella T.
  • Nature Chemical Biology, Vol. 13, Issue 4
  • DOI: 10.1038/nchembio.2331

SAXS-Oriented Ensemble Refinement of Flexible Biomolecules
journal, April 2017


The entropic force generated by intrinsically disordered segments tunes protein function
journal, November 2018

  • Keul, Nicholas D.; Oruganty, Krishnadev; Schaper Bergman, Elizabeth T.
  • Nature, Vol. 563, Issue 7732
  • DOI: 10.1038/s41586-018-0699-5

Force field development and simulations of intrinsically disordered proteins
journal, February 2018


Regulation and aggregation of intrinsically disordered peptides
journal, February 2015

  • Levine, Zachary A.; Larini, Luca; LaPointe, Nichole E.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 9
  • DOI: 10.1073/pnas.1418155112

On the statistical equivalence of restrained-ensemble simulations with the maximum entropy method
journal, February 2013

  • Roux, Benoît; Weare, Jonathan
  • The Journal of Chemical Physics, Vol. 138, Issue 8
  • DOI: 10.1063/1.4792208

Structural investigation on the intrinsically disordered N-terminal region of HPV16 E7 protein
journal, August 2016


CIDER: Resources to Analyze Sequence-Ensemble Relationships of Intrinsically Disordered Proteins
journal, January 2017


Influence of Density Functionals and Basis Sets on One-Bond Carbon−Carbon NMR Spin−Spin Coupling Constants
journal, February 2008

  • Suardíaz, R.; Pérez, C.; Crespo-Otero, R.
  • Journal of Chemical Theory and Computation, Vol. 4, Issue 3
  • DOI: 10.1021/ct7003287

Orientational Order and Dynamics of Hydration Water in a Single Crystal of Bovine Pancreatic Trypsin Inhibitor
journal, August 1999


Free Energy Surface of an Intrinsically Disordered Protein: Comparison between Temperature Replica Exchange Molecular Dynamics and Bias-Exchange Metadynamics
journal, May 2015

  • Zerze, Gül H.; Miller, Cayla M.; Granata, Daniele
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 6
  • DOI: 10.1021/acs.jctc.5b00047

The Disordered Region of the HCV Protein NS5A: Conformational Dynamics, SH3 Binding, and Phosphorylation
journal, October 2015


How do disordered regions achieve comparable functions to structured domains?: Functional Relevance of IDRs
journal, May 2015

  • Latysheva, Natasha S.; Flock, Tilman; Weatheritt, Robert J.
  • Protein Science, Vol. 24, Issue 6
  • DOI: 10.1002/pro.2674

Exploring Free-Energy Landscapes of Intrinsically Disordered Proteins at Atomic Resolution Using NMR Spectroscopy
journal, December 2013

  • Jensen, Malene Ringkjøbing; Zweckstetter, Markus; Huang, Jie-rong
  • Chemical Reviews, Vol. 114, Issue 13
  • DOI: 10.1021/cr400688u