Frustration-guided motion planning reveals conformational transitions in proteins
Abstract
Proteins exist as conformational ensembles, exchanging between substates to perform their function. Advances in experimental techniques yield unprecedented access to structural snapshots of their conformational landscape. However, computationally modeling how proteins use collective motions to transition between substates is challenging owing to a rugged landscape and large energy barriers. Here in this paper, we present a new, robotics-inspired motion planning procedure called dCCRRT that navigates the rugged landscape between substates by introducing dynamic, interatomic constraints to modulate frustration. The constraints balance non-native contacts and flexibility, and instantaneously redirect the motion towards sterically favorable conformations. On a test set of eight proteins determined in two conformations separated by, on average, 7.5Å root mean square deviation (RMSD), our pathways reduced the Cα atom RMSD to the goal conformation by 78%, outperforming peer methods. Additionally, we then applied dCC-RRT to examine how collective, small-scale motions of four side-chains in the active site of cyclophilin A propagate through the protein. dCC-RRT uncovered a spatially contiguous network of residues linked by steric interactions and collective motion connecting the active site to a recently proposed, non-canonical capsid binding site 25Å away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC-RRT can reveal detailed, all-atom molecular mechanismsmore »
- Authors:
-
[3]
- University of Erlangen-Nuremberg, Erlangen (Germany). Chair of Applied Dynamics
- Stanford Univ., CA (United States). Department of Molecular and Cellular Physiology; SLAC National Accelerator Lab., Menlo Park, CA (United States). Biosciences Division
- SLAC National Accelerator Lab., Menlo Park, CA (United States). Biosciences Division
- Publication Date:
- Research Org.:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1416322
- Grant/Contract Number:
- AC02-76SF00515; 7, 2014-1; NNF15OC0015268
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proteins
- Additional Journal Information:
- Journal Volume: 85; Journal Issue: 10; Journal ID: ISSN 0887-3585
- Publisher:
- Wiley
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; cyclophilin A; dynamic clash constraints (dCC); Gas; Kino-Geometric sampling (KGS); protein conformational transitions; RRT motion planning
Citation Formats
Budday, Dominik, Fonseca, Rasmus, Leyendecker, Sigrid, and van den Bedem, Henry. Frustration-guided motion planning reveals conformational transitions in proteins. United States: N. p., 2017.
Web. doi:10.1002/prot.25333.
Budday, Dominik, Fonseca, Rasmus, Leyendecker, Sigrid, & van den Bedem, Henry. Frustration-guided motion planning reveals conformational transitions in proteins. United States. https://doi.org/10.1002/prot.25333
Budday, Dominik, Fonseca, Rasmus, Leyendecker, Sigrid, and van den Bedem, Henry. Wed .
"Frustration-guided motion planning reveals conformational transitions in proteins". United States. https://doi.org/10.1002/prot.25333. https://www.osti.gov/servlets/purl/1416322.
@article{osti_1416322,
title = {Frustration-guided motion planning reveals conformational transitions in proteins},
author = {Budday, Dominik and Fonseca, Rasmus and Leyendecker, Sigrid and van den Bedem, Henry},
abstractNote = {Proteins exist as conformational ensembles, exchanging between substates to perform their function. Advances in experimental techniques yield unprecedented access to structural snapshots of their conformational landscape. However, computationally modeling how proteins use collective motions to transition between substates is challenging owing to a rugged landscape and large energy barriers. Here in this paper, we present a new, robotics-inspired motion planning procedure called dCCRRT that navigates the rugged landscape between substates by introducing dynamic, interatomic constraints to modulate frustration. The constraints balance non-native contacts and flexibility, and instantaneously redirect the motion towards sterically favorable conformations. On a test set of eight proteins determined in two conformations separated by, on average, 7.5Å root mean square deviation (RMSD), our pathways reduced the Cα atom RMSD to the goal conformation by 78%, outperforming peer methods. Additionally, we then applied dCC-RRT to examine how collective, small-scale motions of four side-chains in the active site of cyclophilin A propagate through the protein. dCC-RRT uncovered a spatially contiguous network of residues linked by steric interactions and collective motion connecting the active site to a recently proposed, non-canonical capsid binding site 25Å away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC-RRT can reveal detailed, all-atom molecular mechanisms for small and large amplitude motions.Source code and binaries are freely available at https://github.com/ExcitedStates/KGS/.},
doi = {10.1002/prot.25333},
journal = {Proteins},
number = 10,
volume = 85,
place = {United States},
year = {Wed Jul 12 00:00:00 EDT 2017},
month = {Wed Jul 12 00:00:00 EDT 2017}
}
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Works referenced in this record:
Hidden alternative structures of proline isomerase essential for catalysis
journal, December 2009
- Fraser, James S.; Clarkson, Michael W.; Degnan, Sheena C.
- Nature, Vol. 462, Issue 7273
Rapid calculation of first and second derivatives of conformational energy with respect to dihedral angles for proteins general recurrent equations
journal, January 1984
- Abe, H.; Braun, W.; Noguti, T.
- Computers & Chemistry, Vol. 8, Issue 4
Zipping and Unzipping of Adenylate Kinase: Atomistic Insights into the Ensemble of Open↔Closed Transitions
journal, November 2009
- Beckstein, Oliver; Denning, Elizabeth J.; Perilla, Juan R.
- Journal of Molecular Biology, Vol. 394, Issue 1
Fast, clash-free RNA conformational morphing using molecular junctions
journal, March 2017
- Héliou, Amélie; Budday, Dominik; Fonseca, Rasmus
- Bioinformatics, Vol. 33, Issue 14
Satisfying Hydrogen Bonding Potential in Proteins
journal, May 1994
- McDonald, Ian K.; Thornton, Janet M.
- Journal of Molecular Biology, Vol. 238, Issue 5
Sampling-based exploration of folded state of a protein under kinematic and geometric constraints
journal, October 2011
- Yao, Peggy; Zhang, Liangjun; Latombe, Jean-Claude
- Proteins: Structure, Function, and Bioinformatics, Vol. 80, Issue 1
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
Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study
journal, September 2014
- Buchenberg, Sebastian; Knecht, Volker; Walser, Reto
- The Journal of Physical Chemistry B, Vol. 118, Issue 47
Protein folding by motion planning
journal, November 2005
- Thomas, Shawna; Song, Guang; Amato, Nancy M.
- Physical Biology, Vol. 2, Issue 4
On the Characterization of Protein Native State Ensembles
journal, March 2007
- Shehu, Amarda; Kavraki, Lydia E.; Clementi, Cecilia
- Biophysical Journal, Vol. 92, Issue 5
Tracing conformational changes in proteins
journal, January 2010
- Haspel, Nurit; Moll, Mark; Baker, Matthew L.
- BMC Structural Biology, Vol. 10, Issue Suppl 1
Discrete molecular dynamics: Discrete Molecular Dynamics
journal, January 2011
- Proctor, Elizabeth A.; Ding, Feng; Dokholyan, Nikolay V.
- Wiley Interdisciplinary Reviews: Computational Molecular Science, Vol. 1, Issue 1
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
Coupled Motions in β 2 AR:Gαs Conformational Ensembles
journal, February 2016
- Pachov, Dimitar V.; Fonseca, Rasmus; Arnol, Damien
- Journal of Chemical Theory and Computation, Vol. 12, Issue 3
Finding Conformational Transition Pathways from Discrete Molecular Dynamics Simulations
journal, September 2012
- Sfriso, Pedro; Emperador, Agusti; Orellana, Laura
- Journal of Chemical Theory and Computation, Vol. 8, Issue 11
Mapping the Dynamics Landscape of Conformational Transitions in Enzyme: The Adenylate Kinase Case
journal, August 2015
- Li, Dechang; Liu, Ming S.; Ji, Baohua
- Biophysical Journal, Vol. 109, Issue 3
Simulating Protein Motions with Rigidity Analysis
journal, July 2007
- Thomas, Shawna; Tang, Xinyu; Tapia, Lydia
- Journal of Computational Biology, Vol. 14, Issue 6
ElNemo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement
journal, July 2004
- Suhre, K.; Sanejouand, Y. -H.
- Nucleic Acids Research, Vol. 32, Issue Web Server
Conformational Flexibility and Structural Dynamics in GPCR-Mediated G Protein Activation: A Perspective
journal, July 2013
- Preininger, Anita M.; Meiler, Jens; Hamm, Heidi E.
- Journal of Molecular Biology, Vol. 425, Issue 13
Time-resolved serial crystallography captures high-resolution intermediates of photoactive yellow protein
journal, December 2014
- Tenboer, Jason; Basu, Shibom; Zatsepin, Nadia
- Science, Vol. 346, Issue 6214
Probabilistic roadmaps for path planning in high-dimensional configuration spaces
journal, January 1996
- Kavraki, L. E.; Svestka, P.; Latombe, J. -C.
- IEEE Transactions on Robotics and Automation, Vol. 12, Issue 4
NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all-atom normal mode analysis
journal, July 2006
- Lindahl, E.; Azuara, C.; Koehl, P.
- Nucleic Acids Research, Vol. 34, Issue Web Server
Sampling large conformational transitions: adenylate kinase as a testing ground
journal, May 2014
- Seyler, Sean L.; Beckstein, Oliver
- Molecular Simulation, Vol. 40, Issue 10-11
Modeling and design by hierarchical natural moves
journal, January 2012
- Sim, A. Y. L.; Levitt, M.; Minary, P.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 8
On the role of frustration in the energy landscapes of allosteric proteins
journal, January 2011
- Ferreiro, Diego U.; Hegler, Joseph A.; Komives, Elizabeth A.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 9
Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit
journal, October 2015
- Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry
- PLOS Computational Biology, Vol. 11, Issue 10
Using Stochastic Roadmap Simulation to Predict Experimental Quantities in Protein Folding Kinetics: Folding Rates and Phi-Values
journal, June 2007
- Chiang, Tsung-Han; Apaydin, Mehmet Serkan; Brutlag, Douglas L.
- Journal of Computational Biology, Vol. 14, Issue 5
Atomic torsional modal analysis for high-resolution proteins
journal, March 2015
- Tirion, Monique M.; ben-Avraham, Daniel
- Physical Review E, Vol. 91, Issue 3
Transition networks for modeling the kinetics of conformational change in macromolecules
journal, April 2008
- Noé, Frank; Fischer, Stefan
- Current Opinion in Structural Biology, Vol. 18, Issue 2
Rapid Sampling of Molecular Motions with Prior Information Constraints
journal, February 2009
- Raveh, Barak; Enosh, Angela; Schueler-Furman, Ora
- PLoS Computational Biology, Vol. 5, Issue 2
Networks of Dynamic Allostery Regulate Enzyme Function
journal, February 2017
- Holliday, Michael Joseph; Camilloni, Carlo; Armstrong, Geoffrey Stuart
- Structure, Vol. 25, Issue 2
Folding thermodynamics of a model three-helix-bundle protein
journal, December 1997
- Zhou, Y.; Karplus, M.
- Proceedings of the National Academy of Sciences, Vol. 94, Issue 26
Structure of a nanobody-stabilized active state of the β2 adrenoceptor
journal, January 2011
- Rasmussen, Søren G. F.; Choi, Hee-Jung; Fung, Juan Jose
- Nature, Vol. 469, Issue 7329
Discrete molecular dynamics studies of the folding of a protein-like model
journal, November 1998
- Dokholyan, Nikolay V.; Buldyrev, Sergey V.; Stanley, H. Eugene
- Folding and Design, Vol. 3, Issue 6
Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography
journal, September 2015
- Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew
- eLife, Vol. 4
Large Amplitude Elastic Motions in Proteins from a Single-Parameter, Atomic Analysis
journal, August 1996
- Tirion, Monique M.
- Physical Review Letters, Vol. 77, Issue 9
Conformational Substates in Proteins
journal, June 1988
- Frauenfelder, H.; Parak, F.; Young, R. D.
- Annual Review of Biophysics and Biophysical Chemistry, Vol. 17, Issue 1
An NMA-guided path planning approach for computing large-amplitude conformational changes in proteins
journal, July 2007
- Kirillova, Svetlana; Cortés, Juan; Stefaniu, Alin
- Proteins: Structure, Function, and Bioinformatics, Vol. 70, Issue 1
Evolution of New Enzymatic Function by Structural Modulation of Cysteine Reactivity in Pseudomonas fluorescens Isocyanide Hydratase
journal, July 2010
- Lakshminarasimhan, Mahadevan; Madzelan, Peter; Nan, Ruth
- Journal of Biological Chemistry, Vol. 285, Issue 38
Energetic analysis of the rhodopsin–G-protein complex links the α5 helix to GDP release
journal, December 2013
- Alexander, Nathan S.; Preininger, Anita M.; Kaya, Ali I.
- Nature Structural & Molecular Biology, Vol. 21, Issue 1
Protein normal-mode dynamics: Trypsin inhibitor, crambin, ribonuclease and lysozyme
journal, February 1985
- Levitt, Michael; Sander, Christian; Stern, Peter S.
- Journal of Molecular Biology, Vol. 181, Issue 3
Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery
journal, February 2017
- Choy, Meng S.; Li, Yang; Machado, Luciana E. S. F.
- Molecular Cell, Vol. 65, Issue 4
Crystal structure of the β2 adrenergic receptor–Gs protein complex
journal, July 2011
- Rasmussen, Søren G. F.; DeVree, Brian T.; Zou, Yaozhong
- Nature, Vol. 477, Issue 7366
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
Fluctuation Flooding Method (FFM) for accelerating conformational transitions of proteins
journal, March 2014
- Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru
- The Journal of Chemical Physics, Vol. 140, Issue 12
Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site
journal, March 2016
- Liu, Chuang; Perilla, Juan R.; Ning, Jiying
- Nature Communications, Vol. 7, Issue 1
Mapping the Accessible Conformational Landscape of an Insect Carboxylesterase Using Conformational Ensemble Analysis and Kinetic Crystallography
journal, June 2016
- Correy, Galen J.; Carr, Paul D.; Meirelles, Tamara
- Structure, Vol. 24, Issue 6
A path planning approach for computing large-amplitude motions of flexible molecules
journal, June 2005
- Cortes, J.; Simeon, T.; Ruiz de Angulo, V.
- Bioinformatics, Vol. 21, Issue Suppl 1
Smooth continuous transition between tasks on a kinematic control level: Obstacle avoidance as a control problem
journal, September 2013
- Petrič, Tadej; Žlajpah, Leon
- Robotics and Autonomous Systems, Vol. 61, Issue 9
Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics
journal, April 2016
- Maximova, Tatiana; Moffatt, Ryan; Ma, Buyong
- PLOS Computational Biology, Vol. 12, Issue 4
Efficient Algorithms to Explore Conformation Spaces of Flexible Protein Loops
journal, October 2008
- Yao, P.; Dhanik, A.; Marz, N.
- IEEE/ACM Transactions on Computational Biology and Bioinformatics, Vol. 5, Issue 4
SIMS: A Hybrid Method for Rapid Conformational Analysis
journal, July 2013
- Gipson, Bryant; Moll, Mark; Kavraki, Lydia E.
- PLoS ONE, Vol. 8, Issue 7
iMod: multipurpose normal mode analysis in internal coordinates
journal, August 2011
- Lopéz-Blanco, José Ramón; Garzón, José Ignacio; Chacón, Pablo
- Bioinformatics, Vol. 27, Issue 20
The experimental survey of protein-folding energy landscapes
journal, August 2005
- Oliveberg, Mikael; Wolynes, Peter G.
- Quarterly Reviews of Biophysics, Vol. 38, Issue 3
Conformational changes in the G protein Gs induced by the β2 adrenergic receptor
journal, September 2011
- Chung, Ka Young; Rasmussen, Søren G. F.; Liu, Tong
- Nature, Vol. 477, Issue 7366
Elucidating the ensemble of functionally-relevant transitions in protein systems with a robotics-inspired method
journal, January 2013
- Molloy, Kevin; Shehu, Amarda
- BMC Structural Biology, Vol. 13, Issue Suppl 1
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
Unbiased, scalable sampling of protein loop conformations from probabilistic priors
journal, January 2013
- Zhang, Yajia; Hauser, Kris
- BMC Structural Biology, Vol. 13, Issue Suppl 1
Nullspace Sampling with Holonomic Constraints Reveals Molecular Mechanisms of Protein Gαs
journal, July 2015
- Pachov, Dimitar V.; van den Bedem, Henry
- PLOS Computational Biology, Vol. 11, Issue 7
Modeling protein conformational transitions by a combination of coarse-grained normal mode analysis and robotics-inspired methods
journal, January 2013
- Al-Bluwi, Ibrahim; Vaisset, Marc; Siméon, Thierry
- BMC Structural Biology, Vol. 13, Issue Suppl 1
KINARI-Web: a server for protein rigidity analysis
journal, June 2011
- Fox, N.; Jagodzinski, F.; Li, Y.
- Nucleic Acids Research, Vol. 39, Issue suppl
The energy profiles of atomic conformational transition intermediates of adenylate kinase
journal, November 2009
- Feng, Yaping; Yang, Lei; Kloczkowski, Andrzej
- Proteins: Structure, Function, and Bioinformatics, Vol. 77, Issue 3
Characterizing RNA ensembles from NMR data with kinematic models
journal, August 2014
- Fonseca, Rasmus; Pachov, Dimitar V.; Bernauer, Julie
- Nucleic Acids Research, Vol. 42, Issue 15
Geometric analysis characterizes molecular rigidity in generic and non-generic protein configurations
journal, October 2015
- Budday, Dominik; Leyendecker, Sigrid; van den Bedem, Henry
- Journal of the Mechanics and Physics of Solids, Vol. 83
Efficient prediction of protein conformational pathways based on the hybrid elastic network model
journal, February 2014
- Seo, Sangjae; Jang, Yunho; Qian, Pengfei
- Journal of Molecular Graphics and Modelling, Vol. 47
Can Morphing Methods Predict Intermediate Structures?
journal, January 2009
- Weiss, Dahlia R.; Levitt, Michael
- Journal of Molecular Biology, Vol. 385, Issue 2
Works referencing / citing this record:
Collision-free poisson motion planning in ultra high-dimensional molecular conformation spaces
journal, January 2018
- Fonseca, Rasmus; Budday, Dominik; van den Bedem, Henry
- Journal of Computational Chemistry, Vol. 39, Issue 12
Collision-Free Poisson Motion Planning in Ultra High-Dimensional Molecular Conformation Spaces
preprint, January 2016
- Fonseca, Rasmus; Budday, Dominik; Bedem, Henry van den
- arXiv