Data-guided Multi-Map variables for ensemble refinement of molecular movies
Abstract
Driving molecular dynamics simulations with data-guided collective variables offer a promising strategy to recover thermodynamic information from structure-centric experiments. In this study, the three-dimensional electron density of a protein, as it would be determined by cryo-EM or x-ray crystallography, is used to achieve simultaneously free-energy costs of conformational transitions and refined atomic structures. Unlike previous density-driven molecular dynamics methodologies that determine only the best map-model fits, our work employs the recently developed Multi-Map methodology to monitor concerted movements within equilibrium, non-equilibrium, and enhanced sampling simulations. Construction of all-atom ensembles along the chosen values of the Multi-Map variable enables simultaneous estimation of average properties, as well as real-space refinement of the structures contributing to such averages. Using three proteins of increasing size, we demonstrate that biased simulation along the reaction coordinates derived from electron densities can capture conformational transitions between known intermediates. The simulated pathways appear reversible with minimal hysteresis and require only low-resolution density information to guide the transition. The induced transitions also produce estimates for free energy differences that can be directly compared to experimental observables and population distributions. The refined model quality is superior compared to those found in the Protein Data Bank. We find that the bestmore »
- Authors:
-
- Arizona State Univ., Tempe, AZ (United States)
- Arizona State Univ., Tempe, AZ (United States); Purdue Univ., West Lafayette, IN (United States)
- National Institutes of Health (NIH), Bethesda, MD (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
- Sponsoring Org.:
- USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR); National Science Foundation (NSF); National Institutes of Health (NIH)
- OSTI Identifier:
- 1735431
- Grant/Contract Number:
- AC05-00OR22725; MCB-1942763; 2020298734; R01GM095583
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Chemical Physics
- Additional Journal Information:
- Journal Volume: 153; Journal Issue: 21; Journal ID: ISSN 0021-9606
- Publisher:
- American Institute of Physics (AIP)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; steered molecular dynamics; molecular dynamics; x-ray crystallography; proteins; potential energy surfaces; covariance and correlation; free energy; cryogenic electron microscopy; real-space methods
Citation Formats
Vant, John W., Sarkar, Daipayan, Streitwieser, Ellen, Fiorin, Giacomo, Skeel, Robert, Vermaas, Josh V., and Singharoy, Abhishek. Data-guided Multi-Map variables for ensemble refinement of molecular movies. United States: N. p., 2020.
Web. doi:10.1063/5.0022433.
Vant, John W., Sarkar, Daipayan, Streitwieser, Ellen, Fiorin, Giacomo, Skeel, Robert, Vermaas, Josh V., & Singharoy, Abhishek. Data-guided Multi-Map variables for ensemble refinement of molecular movies. United States. https://doi.org/10.1063/5.0022433
Vant, John W., Sarkar, Daipayan, Streitwieser, Ellen, Fiorin, Giacomo, Skeel, Robert, Vermaas, Josh V., and Singharoy, Abhishek. Tue .
"Data-guided Multi-Map variables for ensemble refinement of molecular movies". United States. https://doi.org/10.1063/5.0022433. https://www.osti.gov/servlets/purl/1735431.
@article{osti_1735431,
title = {Data-guided Multi-Map variables for ensemble refinement of molecular movies},
author = {Vant, John W. and Sarkar, Daipayan and Streitwieser, Ellen and Fiorin, Giacomo and Skeel, Robert and Vermaas, Josh V. and Singharoy, Abhishek},
abstractNote = {Driving molecular dynamics simulations with data-guided collective variables offer a promising strategy to recover thermodynamic information from structure-centric experiments. In this study, the three-dimensional electron density of a protein, as it would be determined by cryo-EM or x-ray crystallography, is used to achieve simultaneously free-energy costs of conformational transitions and refined atomic structures. Unlike previous density-driven molecular dynamics methodologies that determine only the best map-model fits, our work employs the recently developed Multi-Map methodology to monitor concerted movements within equilibrium, non-equilibrium, and enhanced sampling simulations. Construction of all-atom ensembles along the chosen values of the Multi-Map variable enables simultaneous estimation of average properties, as well as real-space refinement of the structures contributing to such averages. Using three proteins of increasing size, we demonstrate that biased simulation along the reaction coordinates derived from electron densities can capture conformational transitions between known intermediates. The simulated pathways appear reversible with minimal hysteresis and require only low-resolution density information to guide the transition. The induced transitions also produce estimates for free energy differences that can be directly compared to experimental observables and population distributions. The refined model quality is superior compared to those found in the Protein Data Bank. We find that the best quantitative agreement with experimental free-energy differences is obtained using medium resolution density information coupled to comparatively large structural transitions. Practical considerations for probing the transitions between multiple intermediate density states are also discussed.},
doi = {10.1063/5.0022433},
journal = {Journal of Chemical Physics},
number = 21,
volume = 153,
place = {United States},
year = {Tue Dec 01 00:00:00 EST 2020},
month = {Tue Dec 01 00:00:00 EST 2020}
}
Works referenced in this record:
Continuous changes in structure mapped by manifold embedding of single-particle data in cryo-EM
journal, May 2016
- Frank, Joachim; Ourmazd, Abbas
- Methods, Vol. 100
Structure of the complex between adenylate kinase from Escherichia coli and the inhibitor Ap5A refined at 1.9 Å resolution
journal, March 1992
- Müller, Christoph W.; Schulz, Georg E.
- Journal of Molecular Biology, Vol. 224, Issue 1
Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation
journal, April 2018
- Irwin, Benedict W. J.; Huggins, David J.
- Journal of Chemical Theory and Computation, Vol. 14, Issue 6
Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling
journal, February 1977
- Torrie, G. M.; Valleau, J. P.
- Journal of Computational Physics, Vol. 23, Issue 2
Chemomechanical Coupling in Hexameric Protein–Protein Interfaces Harnesses Energy within V-Type ATPases
journal, December 2016
- Singharoy, Abhishek; Chipot, Christophe; Moradi, Mahmoud
- Journal of the American Chemical Society, Vol. 139, Issue 1
Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations
journal, May 2019
- Ikemura, Shinnosuke; Yasuda, Hiroyuki; Matsumoto, Shingo
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 20
RosettaES: a sampling strategy enabling automated interpretation of difficult cryo-EM maps
journal, June 2017
- Frenz, Brandon; Walls, Alexandra C.; Egelman, Edward H.
- Nature Methods, Vol. 14, Issue 8
BayesWHAM: A Bayesian approach for free energy estimation, reweighting, and uncertainty quantification in the weighted histogram analysis method
journal, May 2017
- Ferguson, Andrew L.
- Journal of Computational Chemistry, Vol. 38, Issue 18
Scalable molecular dynamics with NAMD
journal, January 2005
- Phillips, James C.; Braun, Rosemary; Wang, Wei
- Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
Uncovering a Dynamically Formed Substrate Access Tunnel in Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase
journal, June 2013
- Wang, Po-hung; Bruschi, Maurizio; De Gioia, Luca
- Journal of the American Chemical Society, Vol. 135, Issue 25
Direct observation of ultrafast large-scale dynamics of an enzyme under turnover conditions
journal, March 2018
- Aviram, Haim Yuval; Pirchi, Menahem; Mazal, Hisham
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 13
Direct Derivation of Free Energies of Membrane Deformation and Other Solvent Density Variations From Enhanced Sampling Molecular Dynamics
journal, October 2019
- Fiorin, Giacomo; Marinelli, Fabrizio; Faraldo‐Gómez, José D.
- Journal of Computational Chemistry, Vol. 41, Issue 5
Atomic-accuracy models from 4.5-Å cryo-electron microscopy data with density-guided iterative local refinement
journal, February 2015
- DiMaio, Frank; Song, Yifan; Li, Xueming
- Nature Methods, Vol. 12, Issue 4
Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation
journal, July 2015
- Miao, Yinglong; Feher, Victoria A.; McCammon, J. Andrew
- Journal of Chemical Theory and Computation, Vol. 11, Issue 8
Microsecond Time Scale Rotation Measurements of Single F 1 -ATPase Molecules †
journal, March 2006
- Spetzler, David; York, Justin; Daniel, Douglas
- Biochemistry, Vol. 45, Issue 10
Structure of a human catalytic step I spliceosome
journal, January 2018
- Zhan, Xiechao; Yan, Chuangye; Zhang, Xiaofeng
- Science, Vol. 359, Issue 6375
Computational approaches to detect allosteric pathways in transmembrane molecular machines
journal, July 2016
- Stolzenberg, Sebastian; Michino, Mayako; LeVine, Michael V.
- Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1858, Issue 7
Ab initio molecular dynamics: Propagating the density matrix with Gaussian orbitals
journal, June 2001
- Schlegel, H. Bernhard; Millam, John M.; Iyengar, Srinivasan S.
- The Journal of Chemical Physics, Vol. 114, Issue 22
MolProbity: More and better reference data for improved all-atom structure validation: PROTEIN SCIENCE.ORG
journal, November 2017
- Williams, Christopher J.; Headd, Jeffrey J.; Moriarty, Nigel W.
- Protein Science, Vol. 27, Issue 1
Metainference: A Bayesian inference method for heterogeneous systems
journal, January 2016
- Bonomi, Massimiliano; Camilloni, Carlo; Cavalli, Andrea
- Science Advances, Vol. 2, Issue 1
Computational Recipe for Efficient Description of Large-Scale Conformational Changes in Biomolecular Systems
journal, June 2014
- Moradi, Mahmoud; Tajkhorshid, Emad
- Journal of Chemical Theory and Computation, Vol. 10, Issue 7
Comparison of simple potential functions for simulating liquid water
journal, July 1983
- Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
- The Journal of Chemical Physics, Vol. 79, Issue 2
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
Elastic coupling power stroke mechanism of the F 1 -ATPase molecular motor
journal, May 2018
- Martin, James L.; Ishmukhametov, Robert; Spetzler, David
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 22
Measurement of atom resolvability in cryo-EM maps with Q-scores
journal, February 2020
- Pintilie, Grigore; Zhang, Kaiming; Su, Zhaoming
- Nature Methods, Vol. 17, Issue 3
Large-scale state-dependent membrane remodeling by a transporter protein
journal, December 2019
- Zhou, Wenchang; Fiorin, Giacomo; Anselmi, Claudio
- eLife, Vol. 8
Anisotropic network model: systematic evaluation and a new web interface
journal, August 2006
- Eyal, E.; Yang, L. -W.; Bahar, I.
- Bioinformatics, Vol. 22, Issue 21
Constant pressure molecular dynamics simulation: The Langevin piston method
journal, September 1995
- Feller, Scott E.; Zhang, Yuhong; Pastor, Richard W.
- The Journal of Chemical Physics, Vol. 103, Issue 11
In Silico Study to Identify New Antituberculosis Molecules from Natural Sources by Hierarchical Virtual Screening and Molecular Dynamics Simulations
journal, March 2019
- Pinto, Vinícius; Araújo, Janay; Silva, Rai
- Pharmaceuticals, Vol. 12, Issue 1
“Infostery” analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations
journal, October 2018
- Karami, Yasaman; Bitard-Feildel, Tristan; Laine, Elodie
- Scientific Reports, Vol. 8, Issue 1
Accelerating molecular simulations of proteins using Bayesian inference on weak information
journal, September 2015
- Perez, Alberto; MacCallum, Justin L.; Dill, Ken A.
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 38
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
Flexible Fitting of Atomic Structures into Electron Microscopy Maps Using Molecular Dynamics
journal, May 2008
- Trabuco, Leonardo G.; Villa, Elizabeth; Mitra, Kakoli
- Structure, Vol. 16, Issue 5
Finding Transition Pathways Using the String Method with Swarms of Trajectories
journal, March 2008
- Pan, Albert C.; Sezer, Deniz; Roux, Benoît
- The Journal of Physical Chemistry B, Vol. 112, Issue 11
Improvements in Markov State Model Construction Reveal Many Non-Native Interactions in the Folding of NTL9
journal, March 2013
- Schwantes, Christian R.; Pande, Vijay S.
- Journal of Chemical Theory and Computation, Vol. 9, Issue 4
Structural basis for ligand binding to an enzyme by a conformational selection pathway
journal, May 2017
- Kovermann, Michael; Grundström, Christin; Sauer-Eriksson, A. Elisabeth
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 24
XFEL and NMR Structures of Francisella Lipoprotein Reveal Conformational Space of Drug Target against Tularemia
journal, May 2020
- Zook, James; Shekhar, Mrinal; Hansen, Debra
- Structure, Vol. 28, Issue 5
Ab initio molecular dynamics: basic concepts, current trends and novel applications
journal, December 2002
- Tuckerman, Mark E.
- Journal of Physics: Condensed Matter, Vol. 14, Issue 50
The Adaptive Biasing Force Method: Everything You Always Wanted To Know but Were Afraid To Ask
journal, August 2014
- Comer, Jeffrey; Gumbart, James C.; Hénin, Jérôme
- The Journal of Physical Chemistry B, Vol. 119, Issue 3
Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model
journal, April 2014
- Das, Avisek; Gur, Mert; Cheng, Mary Hongying
- PLoS Computational Biology, Vol. 10, Issue 4
Minimum Free Energy Path of Ligand-Induced Transition in Adenylate Kinase
journal, June 2012
- Matsunaga, Yasuhiro; Fujisaki, Hiroshi; Terada, Tohru
- PLoS Computational Biology, Vol. 8, Issue 6
High-resolution structure determination of sub-100 kDa complexes using conventional cryo-EM
journal, March 2019
- Herzik, Mark A.; Wu, Mengyu; Lander, Gabriel C.
- Nature Communications, Vol. 10, Issue 1
Large-scale allosteric conformational transitions of adenylate kinase appear to involve a population-shift mechanism
journal, November 2007
- Arora, K.; Brooks, C. L.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 47
How to Distinguish Conformational Selection and Induced Fit Based on Chemical Relaxation Rates
journal, September 2016
- Paul, Fabian; Weikl, Thomas R.
- PLOS Computational Biology, Vol. 12, Issue 9
Monte Carlo simulation of differences in free energies of hydration
journal, September 1985
- Jorgensen, William L.; Ravimohan, C.
- The Journal of Chemical Physics, Vol. 83, Issue 6
Binding pathway of retinal to bacterio-opsin: a prediction by molecular dynamics simulations
journal, December 1997
- Isralewitz, B.; Izrailev, S.; Schulten, K.
- Biophysical Journal, Vol. 73, Issue 6
Structure, Function, and Mechanism of the Nickel Metalloenzymes, CO Dehydrogenase, and Acetyl-CoA Synthase
journal, February 2014
- Can, Mehmet; Armstrong, Fraser A.; Ragsdale, Stephen W.
- Chemical Reviews, Vol. 114, Issue 8
The dissociation mechanism of processive cellulases
journal, October 2019
- Vermaas, Josh V.; Kont, Riin; Beckham, Gregg T.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 46
Substrate-engaged 26 S proteasome structures reveal mechanisms for ATP-hydrolysis–driven translocation
journal, October 2018
- de la Peña, Andres H.; Goodall, Ellen A.; Gates, Stephanie N.
- Science, Vol. 362, Issue 6418
AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR
journal, December 1996
- Laskowski, RomanA.; Rullmann, J. AntoonC.; MacArthur, MalcolmW.
- Journal of Biomolecular NMR, Vol. 8, Issue 4
The cryo-EM revolution: fueling the next phase
journal, January 2019
- Subramaniam, Sriram
- IUCrJ, Vol. 6, Issue 1
THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method
journal, October 1992
- Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal
- Journal of Computational Chemistry, Vol. 13, Issue 8
Ni-Zn-[Fe4-S4] and Ni-Ni-[Fe4-S4] clusters in closed and open α subunits of acetyl-CoA synthase/carbon monoxide dehydrogenase
journal, March 2003
- Darnault, Claudine; Volbeda, Anne; Kim, Eun Jin
- Nature Structural & Molecular Biology, Vol. 10, Issue 4
Mechanistic picture for conformational transition of a membrane transporter at atomic resolution
journal, November 2013
- Moradi, M.; Tajkhorshid, E.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 47
Fitting of High-Resolution Structures into Electron Microscopy Reconstruction Images
journal, March 2005
- Fabiola,, Felcy; Chapman, Michael S.
- Structure, Vol. 13, Issue 3
EMRinger: side chain–directed model and map validation for 3D cryo-electron microscopy
journal, August 2015
- Barad, Benjamin A.; Echols, Nathaniel; Wang, Ray Yu-Ruei
- Nature Methods, Vol. 12, Issue 10
Restrained-Ensemble Molecular Dynamics Simulations Based on Distance Histograms from Double Electron–Electron Resonance Spectroscopy
journal, April 2013
- Roux, Benoît; Islam, Shahidul M.
- The Journal of Physical Chemistry B, Vol. 117, Issue 17
Effects of α-tubulin acetylation on microtubule structure and stability
journal, May 2019
- Eshun-Wilson, Lisa; Zhang, Rui; Portran, Didier
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 21
Molecular dynamics flexible fitting: A practical guide to combine cryo-electron microscopy and X-ray crystallography
journal, October 2009
- Trabuco, Leonardo G.; Villa, Elizabeth; Schreiner, Eduard
- Methods, Vol. 49, Issue 2
Exploring transmembrane transport through α-hemolysin with grid-steered molecular dynamics
journal, September 2007
- Wells, David B.; Abramkina, Volha; Aksimentiev, Aleksei
- The Journal of Chemical Physics, Vol. 127, Issue 12
The Current Revolution in Cryo-EM
journal, March 2016
- Egelman, Edward H.
- Biophysical Journal, Vol. 110, Issue 5
Determining protein structures by combining semireliable data with atomistic physical models by Bayesian inference
journal, May 2015
- MacCallum, Justin L.; Perez, Alberto; Dill, Ken A.
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 22
Normal mode based flexible fitting of high-resolution structure into low-resolution experimental data from cryo-EM
journal, September 2004
- Tama, Florence; Miyashita, Osamu; Brooks III, Charles L.
- Journal of Structural Biology, Vol. 147, Issue 3
Equalities and Inequalities: Irreversibility and the Second Law of Thermodynamics at the Nanoscale
journal, March 2011
- Jarzynski, Christopher
- Annual Review of Condensed Matter Physics, Vol. 2, Issue 1
Statistically optimal analysis of samples from multiple equilibrium states
journal, September 2008
- Shirts, Michael R.; Chodera, John D.
- The Journal of Chemical Physics, Vol. 129, Issue 12
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models
journal, October 1992
- Miyamoto, Shuichi; Kollman, Peter A.
- Journal of Computational Chemistry, Vol. 13, Issue 8
Using collective variables to drive molecular dynamics simulations
journal, December 2013
- Fiorin, Giacomo; Klein, Michael L.; Hénin, Jérôme
- Molecular Physics, Vol. 111, Issue 22-23
A smooth particle mesh Ewald method
journal, November 1995
- Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.
- The Journal of Chemical Physics, Vol. 103, Issue 19
Overlap between folding and functional energy landscapes for adenylate kinase conformational change
journal, November 2010
- Olsson, Ulrika; Wolf-Watz, Magnus
- Nature Communications, Vol. 1, Issue 1
Advances in the molecular dynamics flexible fitting method for cryo-EM modeling
journal, May 2016
- McGreevy, Ryan; Teo, Ivan; Singharoy, Abhishek
- Methods, Vol. 100
Constant pressure molecular dynamics algorithms
journal, September 1994
- Martyna, Glenn J.; Tobias, Douglas J.; Klein, Michael L.
- The Journal of Chemical Physics, Vol. 101, Issue 5
Substrate positions and induced-fit in crystalline adenylate kinase
journal, July 1977
- Pai, E. F.; Sachsenheimer, W.; Schirmer, R. H.
- Journal of Molecular Biology, Vol. 114, Issue 1
NMR Structure of Francisella tularensis Virulence Determinant Reveals Structural Homology to Bet v1 Allergen Proteins
journal, June 2015
- Zook, James; Mo, Gina; Sisco, Nicholas J.
- Structure, Vol. 23, Issue 6
Escaping free-energy minima
journal, September 2002
- Laio, A.; Parrinello, M.
- Proceedings of the National Academy of Sciences, Vol. 99, Issue 20
Conformational Dynamics of a Ligand-Free Adenylate Kinase
journal, July 2013
- Song, Hyun Deok; Zhu, Fangqiang
- PLoS ONE, Vol. 8, Issue 7
Automated cryo-EM structure refinement using correlation-driven molecular dynamics
journal, March 2019
- Igaev, Maxim; Kutzner, Carsten; Bock, Lars V.
- eLife, Vol. 8
VMD: Visual molecular dynamics
journal, February 1996
- Humphrey, William; Dalke, Andrew; Schulten, Klaus
- Journal of Molecular Graphics, Vol. 14, Issue 1
Kinetics of Huperzine A Dissociation from Acetylcholinesterase via Multiple Unbinding Pathways
journal, May 2018
- Rydzewski, J.; Jakubowski, R.; Nowak, W.
- Journal of Chemical Theory and Computation, Vol. 14, Issue 6
Predicting the DNA Sequence Dependence of Nanopore Ion Current Using Atomic-Resolution Brownian Dynamics
journal, January 2012
- Comer, Jeffrey; Aksimentiev, Aleksei
- The Journal of Physical Chemistry C, Vol. 116, Issue 5
Trajectories of the ribosome as a Brownian nanomachine
journal, November 2014
- Dashti, Ali; Schwander, Peter; Langlois, Robert
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 49