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Title: All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

Abstract

Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Finally, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets.

Authors:
 [1];  [1];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Beckman Institute, and ‡Department of Physics, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Univ. of Illinois at Urbana-Champaign, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1250973
Alternate Identifier(s):
OSTI ID: 1344922
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Published Article
Journal Name:
Journal of Physical Chemistry Letters
Additional Journal Information:
Journal Name: Journal of Physical Chemistry Letters Journal Volume: 7 Journal Issue: 10; Journal ID: ISSN 1948-7185
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Perilla, Juan R., Hadden, Jodi A., Goh, Boon Chong, Mayne, Christopher G., and Schulten, Klaus. All-Atom Molecular Dynamics of Virus Capsids as Drug Targets. United States: N. p., 2016. Web. doi:10.1021/acs.jpclett.6b00517.
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Perilla, Juan R., Hadden, Jodi A., Goh, Boon Chong, Mayne, Christopher G., & Schulten, Klaus. All-Atom Molecular Dynamics of Virus Capsids as Drug Targets. United States. https://doi.org/10.1021/acs.jpclett.6b00517
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Perilla, Juan R., Hadden, Jodi A., Goh, Boon Chong, Mayne, Christopher G., and Schulten, Klaus. Wed . "All-Atom Molecular Dynamics of Virus Capsids as Drug Targets". United States. https://doi.org/10.1021/acs.jpclett.6b00517.
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@article{osti_1250973,
title = {All-Atom Molecular Dynamics of Virus Capsids as Drug Targets},
author = {Perilla, Juan R. and Hadden, Jodi A. and Goh, Boon Chong and Mayne, Christopher G. and Schulten, Klaus},
abstractNote = {Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Finally, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets.},
doi = {10.1021/acs.jpclett.6b00517},
journal = {Journal of Physical Chemistry Letters},
number = 10,
volume = 7,
place = {United States},
year = {Wed May 04 00:00:00 EDT 2016},
month = {Wed May 04 00:00:00 EDT 2016}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1021/acs.jpclett.6b00517
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Works referenced in this record:

Visualization of a missing link in retrovirus capsid assembly
journal, February 2009

  • Cardone, Giovanni; Purdy, John G.; Cheng, Naiqian
  • Nature, Vol. 457, Issue 7230
  • DOI: 10.1038/nature07724

Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K a Values
journal, June 2011

  • Søndergaard, Chresten R.; Olsson, Mats H. M.; Rostkowski, Michał
  • Journal of Chemical Theory and Computation, Vol. 7, Issue 7
  • DOI: 10.1021/ct200133y

Twenty-five years of nucleic acid simulations
journal, June 2013

Representation of Ion–Protein Interactions Using the Drude Polarizable Force-Field
journal, September 2014

  • Li, Hui; Ngo, Van; Da Silva, Mauricio Chagas
  • The Journal of Physical Chemistry B, Vol. 119, Issue 29
  • DOI: 10.1021/jp510560k

Virus assembly, allostery and antivirals
journal, January 2011

Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors
journal, February 2016

  • Ellis, Christopher R.; Tsai, Cheng-Chieh; Hou, Xinjun
  • The Journal of Physical Chemistry Letters, Vol. 7, Issue 6
  • DOI: 10.1021/acs.jpclett.6b00137

AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
journal, December 2009

  • Morris, Garrett M.; Huey, Ruth; Lindstrom, William
  • Journal of Computational Chemistry, Vol. 30, Issue 16
  • DOI: 10.1002/jcc.21256

Physical Principles in the Construction of Regular Viruses
journal, January 1962

Recent Advances in Polarizable Force Fields for Macromolecules: Microsecond Simulations of Proteins Using the Classical Drude Oscillator Model
journal, September 2014

  • Huang, Jing; Lopes, Pedro E. M.; Roux, Benoît
  • The Journal of Physical Chemistry Letters, Vol. 5, Issue 18
  • DOI: 10.1021/jz501315h

Compensatory Substitutions in the HIV-1 Capsid Reduce the Fitness Cost Associated with Resistance to a Capsid-Targeting Small-Molecule Inhibitor
journal, October 2014

  • Shi, Jiong; Zhou, Jing; Halambage, Upul D.
  • Journal of Virology, Vol. 89, Issue 1
  • DOI: 10.1128/JVI.01411-14

Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry Data
journal, November 2012

  • Wang, Lee-Ping; Chen, Jiahao; Van Voorhis, Troy
  • Journal of Chemical Theory and Computation, Vol. 9, Issue 1
  • DOI: 10.1021/ct300826t

Contributions of Charged Residues in Structurally Dynamic Capsid Surface Loops to Rous Sarcoma Virus Assembly
journal, April 2016

  • Heyrana, Katrina J.; Goh, Boon Chong; Perilla, Juan R.
  • Journal of Virology, Vol. 90, Issue 12
  • DOI: 10.1128/JVI.00378-16

Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics
journal, May 2013

  • Zhao, Gongpu; Perilla, Juan R.; Yufenyuy, Ernest L.
  • Nature, Vol. 497, Issue 7451
  • DOI: 10.1038/nature12162

The SAMPL4 host–guest blind prediction challenge: an overview
journal, March 2014

  • Muddana, Hari S.; Fenley, Andrew T.; Mobley, David L.
  • Journal of Computer-Aided Molecular Design, Vol. 28, Issue 4
  • DOI: 10.1007/s10822-014-9735-1

A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly
journal, May 2005

  • Stray, S. J.; Bourne, C. R.; Punna, S.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 23
  • DOI: 10.1073/pnas.0409732102

The ligand binding mechanism to purine nucleoside phosphorylase elucidated via molecular dynamics and machine learning
journal, January 2015

  • Decherchi, Sergio; Berteotti, Anna; Bottegoni, Giovanni
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms7155

Structural basis of HIV-1 capsid recognition by PF74 and CPSF6
journal, December 2014

  • Bhattacharya, Akash; Alam, Steven L.; Fricke, Thomas
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 52
  • DOI: 10.1073/pnas.1419945112

HIV-1 uncoating: connection to nuclear entry and regulation by host proteins
journal, April 2014

Using Situs for the integration of multi-resolution structures
journal, January 2010

Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing
journal, November 2012

  • Vanommeslaeghe, K.; MacKerell, A. D.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 12
  • DOI: 10.1021/ci300363c

Computation-Guided Discovery of Influenza Endonuclease Inhibitors
journal, November 2013

  • Chen, Eric; Swift, Robert V.; Alderson, Nazilla
  • ACS Medicinal Chemistry Letters, Vol. 5, Issue 1
  • DOI: 10.1021/ml4003474

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
journal, January 2009

  • Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.
  • Journal of Computational Chemistry
  • DOI: 10.1002/jcc.21367

Molecular Architecture of the Retroviral Capsid
journal, May 2016

MATCH: An atom-typing toolset for molecular mechanics force fields
journal, November 2011

  • Yesselman, Joseph D.; Price, Daniel J.; Knight, Jennifer L.
  • Journal of Computational Chemistry, Vol. 33, Issue 2
  • DOI: 10.1002/jcc.21963

Classical Electrostatics for Biomolecular Simulations
journal, August 2013

  • Cisneros, G. Andrés; Karttunen, Mikko; Ren, Pengyu
  • Chemical Reviews, Vol. 114, Issue 1
  • DOI: 10.1021/cr300461d

Constant-pH Hybrid Nonequilibrium Molecular Dynamics–Monte Carlo Simulation Method
journal, July 2015

  • Chen, Yunjie; Roux, Benoît
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 8
  • DOI: 10.1021/acs.jctc.5b00261

X-Ray Structures of the Hexameric Building Block of the HIV Capsid
journal, June 2009

Rapid parameterization of small molecules using the force field toolkit
journal, September 2013

  • Mayne, Christopher G.; Saam, Jan; Schulten, Klaus
  • Journal of Computational Chemistry, Vol. 34, Issue 32
  • DOI: 10.1002/jcc.23422

Molecular Dynamics Simulations of Nucleic Acids. From Tetranucleotides to the Ribosome
journal, May 2014

  • Šponer, Jiří; Banáš, Pavel; Jurečka, Petr
  • The Journal of Physical Chemistry Letters, Vol. 5, Issue 10
  • DOI: 10.1021/jz500557y

Development and testing of a general amber force field
journal, January 2004

  • Wang, Junmei; Wolf, Romain M.; Caldwell, James W.
  • Journal of Computational Chemistry, Vol. 25, Issue 9
  • DOI: 10.1002/jcc.20035

Small-Molecule Effectors of Hepatitis B Virus Capsid Assembly Give Insight into Virus Life Cycle
journal, August 2008

  • Bourne, C.; Lee, S.; Venkataiah, B.
  • Journal of Virology, Vol. 82, Issue 20
  • DOI: 10.1128/JVI.01360-08

Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges
journal, November 2012

  • Vanommeslaeghe, K.; Raman, E. Prabhu; MacKerell, A. D.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 12
  • DOI: 10.1021/ci3003649

HIV-1 assembly, release and maturation
journal, June 2015

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion
journal, February 2015

  • Zeng, Xiancheng; Mukhopadhyay, Suchetana; Brooks, Charles L.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 7
  • DOI: 10.1073/pnas.1414190112

UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004

  • Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
  • Journal of Computational Chemistry, Vol. 25, Issue 13
  • DOI: 10.1002/jcc.20084

Flexible Fitting of Atomic Structures into Electron Microscopy Maps Using Molecular Dynamics
journal, May 2008

Structural Convergence between Cryo-EM and NMR Reveals Intersubunit Interactions Critical for HIV-1 Capsid Function
journal, November 2009

Atomic-level modelling of the HIV capsid
journal, January 2011

  • Pornillos, Owen; Ganser-Pornillos, Barbie K.; Yeager, Mark
  • Nature, Vol. 469, Issue 7330
  • DOI: 10.1038/nature09640

Molecular dynamics simulations and drug discovery
journal, October 2011

Two Pathways Mediate Interdomain Allosteric Regulation in Pin1
journal, January 2015

Characterization of Poliovirus Variants Selected for Resistance to the Antiviral Compound V-073
journal, August 2012

  • Liu, Hong-Mei; Roberts, Jason A.; Moore, Deborah
  • Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 11
  • DOI: 10.1128/AAC.00539-12

HIV-1 capsid: the multifaceted key player in HIV-1 infection
journal, July 2015

  • Campbell, Edward M.; Hope, Thomas J.
  • Nature Reviews Microbiology, Vol. 13, Issue 8
  • DOI: 10.1038/nrmicro3503

The future of molecular dynamics simulations in drug discovery
journal, December 2011

  • Borhani, David W.; Shaw, David E.
  • Journal of Computer-Aided Molecular Design, Vol. 26, Issue 1
  • DOI: 10.1007/s10822-011-9517-y

Neuraminidase Inhibitors for Influenza
journal, September 2005

Comparative Protein Structure Modeling Using Modeller
journal, September 2006

Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly
journal, October 2014

The Future of HIV-1 Therapeutics: Resistance Is Futile?
book, January 2015

  • Torbett, Bruce E.; Goodsell, David S.; Richman, Douglas D.
  • Current Topics in Microbiology and Immunology
  • DOI: 10.1007/978-3-319-18518-7

All-atom polarizable force field for DNA based on the classical drude oscillator model
journal, April 2014

  • Savelyev, Alexey; MacKerell, Alexander D.
  • Journal of Computational Chemistry, Vol. 35, Issue 16
  • DOI: 10.1002/jcc.23611

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection
journal, November 2015

Global Structural Changes in Hepatitis B Virus Capsids Induced by the Assembly Effector HAP1
journal, August 2006

  • Bourne, C. R.; Finn, M. G.; Zlotnick, A.
  • Journal of Virology, Vol. 80, Issue 22
  • DOI: 10.1128/JVI.00933-06

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention
journal, December 2010

X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability
journal, June 2015

  • Gres, Anna T.; Kirby, Karen A.; KewalRamani, Vineet N.
  • Science, Vol. 349, Issue 6243
  • DOI: 10.1126/science.aaa5936

Dynamic allostery governs cyclophilin A–HIV capsid interplay
journal, November 2015

  • Lu, Manman; Hou, Guangjin; Zhang, Huilan
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 47
  • DOI: 10.1073/pnas.1516920112

Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins
journal, August 2013

  • Shi, Yue; Xia, Zhen; Zhang, Jiajing
  • Journal of Chemical Theory and Computation, Vol. 9, Issue 9
  • DOI: 10.1021/ct4003702

Macromolecular Modeling with Rosetta
journal, June 2008

Magic Angle Spinning NMR Reveals Sequence-Dependent Structural Plasticity, Dynamics, and the Spacer Peptide 1 Conformation in HIV-1 Capsid Protein Assemblies
journal, November 2013

  • Han, Yun; Hou, Guangjin; Suiter, Christopher L.
  • Journal of the American Chemical Society, Vol. 135, Issue 47
  • DOI: 10.1021/ja406907h

Capsid proteins of enveloped viruses as antiviral drug targets
journal, April 2014

pH-REMD Simulations Indicate That the Catalytic Aspartates of HIV-1 Protease Exist Primarily in a Monoprotonated State
journal, October 2014

  • McGee, T. Dwight; Edwards, Jesse; Roitberg, Adrian E.
  • The Journal of Physical Chemistry B, Vol. 118, Issue 44
  • DOI: 10.1021/jp504011c

Molecular dynamics simulations of large macromolecular complexes
journal, April 2015

  • Perilla, Juan R.; Goh, Boon Chong; Cassidy, C. Keith
  • Current Opinion in Structural Biology, Vol. 31
  • DOI: 10.1016/j.sbi.2015.03.007

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
  • DOI: 10.1038/ncomms10714

A model for cofactor use during HIV-1 reverse transcription and nuclear entry
journal, February 2014

Toward Improved Force-Field Accuracy through Sensitivity Analysis of Host-Guest Binding Thermodynamics
journal, July 2015

  • Yin, Jian; Fenley, Andrew T.; Henriksen, Niel M.
  • The Journal of Physical Chemistry B, Vol. 119, Issue 32
  • DOI: 10.1021/acs.jpcb.5b04262

ViennaRNA Package 2.0
journal, November 2011

  • Lorenz, Ronny; Bernhart, Stephan H.; Höner zu Siederdissen, Christian
  • Algorithms for Molecular Biology, Vol. 6, Issue 1
  • DOI: 10.1186/1748-7188-6-26

VIPERdb2: an enhanced and web API enabled relational database for structural virology
journal, January 2009

  • Carrillo-Tripp, M.; Shepherd, C. M.; Borelli, I. A.
  • Nucleic Acids Research, Vol. 37, Issue Database
  • DOI: 10.1093/nar/gkn840

Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism: Explicit Solvent CPHMD of Proteins
journal, January 2014

  • Goh, Garrett B.; Hulbert, Benjamin S.; Zhou, Huiqing
  • Proteins: Structure, Function, and Bioinformatics, Vol. 82, Issue 7
  • DOI: 10.1002/prot.24499

Dynamical networks in tRNA:protein complexes
journal, April 2009

  • Sethi, A.; Eargle, J.; Black, A. A.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 16
  • DOI: 10.1073/pnas.0810961106

NetworkView: 3D display and analysis of protein{middle dot}RNA interaction networks
journal, September 2012

Computational approaches to mapping allosteric pathways
journal, April 2014

  • Feher, Victoria A.; Durrant, Jacob D.; Van Wart, Adam T.
  • Current Opinion in Structural Biology, Vol. 25
  • DOI: 10.1016/j.sbi.2014.02.004

H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations
journal, May 2012

  • Anandakrishnan, R.; Aguilar, B.; Onufriev, A. V.
  • Nucleic Acids Research, Vol. 40, Issue W1
  • DOI: 10.1093/nar/gks375

Atomic Modeling of an Immature Retroviral Lattice Using Molecular Dynamics and Mutagenesis
journal, August 2015

Rational Prediction with Molecular Dynamics for Hit Identification
journal, September 2012

  • E. Nichols, Sara; V. Swift, Robert; E. Amaro, Rommie
  • Current Topics in Medicinal Chemistry, Vol. 12, Issue 18
  • DOI: 10.2174/156802612804910313

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization
journal, October 2010

Cyclophilin A: a key player for human disease
journal, October 2013

  • Nigro, P.; Pompilio, G.; Capogrossi, M. C.
  • Cell Death & Disease, Vol. 4, Issue 10
  • DOI: 10.1038/cddis.2013.410

Systematic Improvement of a Classical Molecular Model of Water
journal, August 2013

  • Wang, Lee-Ping; Head-Gordon, Teresa; Ponder, Jay W.
  • The Journal of Physical Chemistry B, Vol. 117, Issue 34
  • DOI: 10.1021/jp403802c

VMD: Visual molecular dynamics
journal, February 1996

Constant pH Replica Exchange Molecular Dynamics in Explicit Solvent Using Discrete Protonation States: Implementation, Testing, and Validation
journal, February 2014

  • Swails, Jason M.; York, Darrin M.; Roitberg, Adrian E.
  • Journal of Chemical Theory and Computation, Vol. 10, Issue 3
  • DOI: 10.1021/ct401042b
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