Available online at www.sciencedirect.com
ScienceDirect
All-atom virus simulations
Jodi A Hadden and Juan R Perilla
The constant threat of viral disease can be combated by the All-atom molecular dynamics (MD) simulations, often
development of novel vaccines and therapeutics designed to referred to as the ‘computational microscope’, remain
disrupt key features of virus structure or infection cycle the only method capable of elucidating the dynamical
processes. Such development relies on high-resolution properties of biomolecules within their physiological
characterization of viruses and their dynamical behaviors, environments at full chemical resolution [1 ]. Modern
which are often challenging to obtain solely by experiment. In supercomputers and MD simulation codes enable
response, all-atom molecular dynamics simulations are widely researchers to investigate the nuances of virus structure
leveraged to study the structural components of viruses, and dynamics, even for very large components of virus
leading to some of the largest simulation endeavors undertaken structure [2].
to date. The present work reviews exemplary all-atom
simulation work on viruses, as well as progress toward Most all-atom MD simulation studies of viruses have
simulating entire virions. focused on their protein-based components, particularly
envelope proteins, viroporins, capsids, and accessory pro-
Address teins or enzymes. Some work has leveraged MD simula-
Department of Chemistry and Biochemistry, University of Delaware, tions to construct complete atomistic models of viral
Newark, DE 19716, United States proteins or their assemblies by integrating experimental
data. Other work has taken advantage of MD simulations
Corresponding author: Hadden, Jodi A ([email protected])
to characterize, under native conditions, the chemical-
physical properties of such structures through analysis of
Current Opinion in Virology 2018, 31:82–91 their dynamics and influence on surrounding solvent. The
overarching goals of virus simulation endeavors are to
This review comes from a themed issue on Virus structure and
expression reveal critical aspects of virus structure or mechanistic
insights into their function that can be targeted for novel
Edited by Kay Gru¨ newald and Thomas Krey
disease treatments. Here, exemplary all-atom simulations
For a complete overview see the Issue and the Editorial
of viruses are briefly reviewed, and progress toward sim-
Available online 1st September 2018
ulating entire virions at atomistic detail is discussed.
https://doi.org/10.1016/j.coviro.2018.08.007
1879-6257/ã 2018 Elsevier B.V. All rights reserved. Envelope proteins
The first stage of viral infection is cell entry. Often, this
process begins with adhesion of the virus to the host cell
via receptor binding. In enveloped viruses, receptor
binding is mediated by membrane-embedded surface
proteins, which typically also represent the major anti-
Introduction gens of the virus and may participate in virus–host mem-
brane fusion. Other envelope proteins play a role in viral
Viruses are a constant threat to human health, as well as egress. The motivation to elucidate the molecular deter-
the health of our domesticated animals and agriculture. minants of receptor recognition, as well as the antigenic
Often, viral infections are challenging to treat due to and fusogenic properties of envelope proteins, have ren-
limited therapeutic options. Although vaccines are effec- dered them of great interest for study with MD
tive at preventing or reducing the severity of viral disease, simulations.
protective vaccines against fewer than 20 different viruses
are currently available (WHO). Further, the high muta- A broadly studied viral envelope protein is the influenza A
tion rates of some viruses necessitate that vaccines be hemagglutinin (HA) trimer (Figure 1a), which is respon-
updated annually, or that new antiviral treatments be sible for cellular adhesion and membrane fusion. Much
constantly realized to continue disease management in work on HA has been aimed at understanding its speci-
chronically infected individuals. ficity for host cell receptor glycans, which is an important
factor in the avian-human transmission barrier [6,7].
The rational development of novel prophylactic and Characterization of receptor binding may support the
therapeutic interventions against viral pathogens depends development of adhesion-inhibiting drugs.
on detailed knowledge of virus structure, infection cycle
processes, and the conformational dynamics that link All-atom MD simulations have been applied to numerous
structures to their functional roles in these processes. crystal complexes of HAs with receptor analogues to
Current Opinion in Virology 2018, 31:82–91 www.sciencedirect.com
All-atom simulations of viruses Hadden and Perilla 83
Figure 1
(a)NA (b) (c) RNA
RNA
RNA Vpu RT
capsid
HA envelope envelope matrix
Current Opinion in Virology
Schematic illustrations of viruses whose protein components have been heavily studied using all-atom MD simulations. (a) Influenza A virus virion,
average diameter of 120 nm [3]. Hemagglutinin (HA), neuraminidase (NA), and the matrix protein 2 viroporin (M2) are embedded within the viral
envelope, which surrounds the matrix protein 1 (M1) assembly and encloses the RNA. (b) Mature HIV-1 virion, average diameter of 145 nm [4]. The
envelope protein (Env) and viroporin (Vpu) are embedded within the viral envelope, which surrounds the matrix protein assembly and encloses the
RNA-containing capsid. The virus also carries copies of a protease and reverse transcriptase (RT). (c) STMV virion, diameter of 17 nm [5 ]. STMV
is a non-enveloped virus, composed only of the RNA-containing capsid.
characterize binding mode dynamics, as well as to study virions. Several compounds that mimic the native sub-
recognition and specificity based on bound receptor con- strate of NA and bind to inhibit its action have been
formations and interaction profiles [8–12]. Recent model- licensed for use as antiviral drugs for the treatment of
ing and simulation work has also revealed that HA recep- influenza A (i.e. tamivir and zanamivir) [33]. The majority
tor specificity may depend on extended glycan structure of simulation work on NA has focused on exploiting it as a
and the ability to accommodate bidentate binding to drug target. In some cases, all-atom simulations have
biantennary glycans [13,14]. MD simulations have been been employed to characterize the conformational
further employed to evaluate the effects of HA mutations dynamics of NA from the perspective of designing novel
that alter receptor binding and specificity [15,16] and to drug compounds or elucidating the determinants of
study HA-antibody recognition and escape [17,18]. ligand recognition and inhibition [34–37]. In other cases,
simulations of NA have been used as part of computa-
Notably, HA is glycosylated, with N-glycans contributing tional screening protocols to discover new druggable hot
around 20% of its molecular weight [6]. All-atom simula- spots or inhibitor leads [38–40]. Additional studies have
tions of glycosylated HAs have been used to probe the provided insights into the mechanisms of drug resistance
influence of glycosylation on receptor binding [19], to [41–43], the role of calcium in NA stability and drug
provide insight into accessibility of glycan-remodeling binding [44], and the structural basis for increased viru-
enzymes [20], and to characterize interactions between lence of NA stalk-deletion mutants [45 ].
HA and lung surfactant protein D, an innate immune
lectin that neutralizes influenza A via attachment to HA Another well-studied envelope protein is the human
glycans [21 ]. immunodeficiency virus type 1 (HIV-1) envelope (Env)
trimer (Figures 1b and 2 d), which mediates cellular
HA initiates fusion of the viral envelope and host mem- adhesion and membrane fusion. All-atom MD simula-
branes following cell adhesion and endocytosis, when tions have been employed to characterize the conforma-
endosomal acidification triggers it to undergo a confor- tional properties of Env, particularly its V3 variable
mational change. The mechanism of HA-mediated mem- domain, a critical determinant of CD4 receptor binding
brane fusion has been extensively studied with simula- [46,47]. Other simulation work on Env has focused on
tion approaches, including characterization of fusion identifying correlated motions that may underlie alloste-
peptide dynamics, interactions with the host membrane, ric communication networks within the protein [47–50].
and structural effects of reduced pH [22–32]. The transmembrane domain and fusion peptide of Env
have also been extensively investigated with MD simula-
The secondary surface antigen of the influenza A virus is tions to explore conformational variability and membrane
the neuraminidase (NA) tetramer (Figure 1a), which interactions, providing insights into the mechanism of
cleaves host cell glycans to allow escape of progeny membrane fusion [51–56].
www.sciencedirect.com Current Opinion in Virology 2018, 31:82–91
84 Virus structure and expression
Importantly, Env is heavily glycosylated, with N -glycans been aimed at characterizing drug binding and channel
accounting for roughly 50% of its molecular weight [57]. inhibition [84,85,90], probing the mechanisms of drug
These glycans form a shield around Env, cloaking it from resistance [91,92], and designing new inhibitors against
the host immune system, and may also influence the drug-resistant mutants [93,94].
binding affinity of CD4. The glycan shield is of great
interest as a target for broadly-neutralizing antibody and Other viroporins that have been examined using all-atom
vaccine design [57], and can only be accurately described MD simulations include the viral protein U (Vpu) of HIV-
with simulations that encompass chemical detail. Several 1 (Figures 1b and 2 a). Various early modeling and
all-atom MD studies have investigated the effects of simulation studies of Vpu [95] led to evaluation of its
glycosylation on the conformation and dynamics of Env preferred oligomeric state and all-atom investigation of its
variable domains V1, V2, and V3, as well as implications dynamics and channel activity [96]. All-atom simulations
for receptor and antibody binding [58–60]. More recent were also applied to develop a model for the Paramecium
work has used computational modeling and simulation to bursaria chlorella virus type 1 (PBCV-1) Kcv potassium
produce fully glycosylated Env trimers, with the goals of channel to probe structure–function relationships [97,98]
characterizing the dynamical behavior of the glycan and elucidate its mechanism of ion transport [99]. More
shield and determining its impact on antibody elicitation, recently, all-atom simulations were employed to deter-
recognition, and binding [50,61 ,62,63]. mine the structure of the hepatitis C virus (HCV) p7
viroporin monomer [100] and to model various channel
Beyond influenza A and HIV-1, all-atom MD simulations oligomer states, enabling characterization of their dynam-
have also been applied to study the envelope proteins of ics and conductance properties [101 ,102,103,104,105].
several other viruses. Such work has included investiga-
tions of the effects of varying pH on the dengue virus [64– Capsids
69] and vesicular stomatitis virus (VSV) [70] envelope Many viruses package their genome within a remarkable
proteins, structure and host membrane interactions for protein shell called a capsid. Often, capsids play key
the Ebola virus [71–73] and herpes simplex virus (HSV) functional roles in delivering the viral genome to the host
[74] envelope protein fusion peptides, solution dynamics cell nucleus, rendering them of great interest as drug
of human parainfluenza virus type 3 (HPIV-3) hemagglu- targets. Capsids generally represent the largest protein
tinin-neuraminidase [75], and conformational flexibility components of virus structures, and simulations of intact
in the hepatitis C virus (HCV) E2 envelope protein capsids have accounted for the most substantial all-atom
[76,77]. virus simulations yet published [106,2]. Work by Perilla
et al. has clearly demonstrated the need for chemical
Viroporins detail to facilitate accurate simulation studies of virus
Enveloped viruses can encode another class of mem- capsids as drug targets [107 ].
brane-embedded proteins, called viroporins, that play
diverse roles in their respective viral infection cycles. The first all-atom simulation of a complete virus capsid
Viroporins are small, hydrophobic proteins that oligomer- was based on satellite tobacco mosaic virus (STMV,
ize within the envelope to form hydrophilic channels, Figures 1c and 2 g) and encompassed a landmark particle
capable of transporting ionic species and small molecules count of 1 million atoms with solvent [108 ]. Both an
[78]. The essential activities of these channels, their empty and genome-containing capsid were investigated
druggability, and potential as models to understand trans- over 10–13 ns. With packaged RNA, the simulated capsid
port mechanisms within the human cell, have rendered maintained structural integrity and exhibited only minor
them of long-standing interest for study with MD deviations from icosahedral symmetry. Without RNA, the
simulations. simulated capsid rapidly broke symmetry and began to
implode. The results of the work strongly suggest that
The most widely studied viroporin, from a computational RNA is responsible for nucleating assembly of STMV
perspective, is the influenza A matrix protein 2 (M2) ion virions.
channel (Figure 1a), which transports protons across the
viral envelope following endosomal acidification to pre- Prior to work on STMV, simulations of complete capsids
pare the particle for host membrane fusion and subse- were approximated using rotational symmetry boundary
quent genome release [79]. All-atom MD simulations conditions, which exploit the icosahedral symmetry of
have been broadly employed to study M2 channel acti- capsid structures to model, at least in effect, a complete
vation, gating, and proton permeation [80–86], as well as capsid using only the capsid asymmetric unit [106]. As
investigate the relationship between pH and channel time has progressed, all-atom simulations of intact capsids
conductance [87,88] and internal water structure [89]. have become increasingly accessible. Notably, such work
Adamantane drug compounds (i.e. amantadine and has included characterization of the stress-response of the
rimantidine) are known to inhibit M2 channel activity southern bean mosaic virus (SBMV) capsid [109], valida-
[79]. Additional all-atom MD simulation work on M2 has tion of multi-scale modeling approaches based on the
Current Opinion in Virology 2018, 31:82–91 www.sciencedirect.com
All-atom simulations of viruses Hadden and Perilla 85
Sesbania mosaic virus (SeMV) capsid [110], derivation of guided MD simulations [118 ]. This landmark simula-
a complete atomic model for the rabbit hemorrhagic tion endeavor, encompassing 64 million atoms with sol-
disease virus (RHDV) capsid [111], and examination of vent, overcame the challenges of HIV-1 capsid size and
the interplay between solvent and ions and the porcine asymmetric architecture to generate the first chemically
circovirus type 2 (PCV2) capsid [112,113]. complete model. The results of the study revealed key
structural elements defining pentamer–hexamer and
The first all-atom simulation of a virus capsid to explore hexamer–hexamer interfaces within the capsid and pro-
the microsecond timescale was based on an empty model duced a much-needed platform to enable investigation of
of satellite tobacco necrosis virus (STNV), which encom- capsid function and targeted drug development. Notably,
passed 1.2 million atoms with solvent [114 ]. Like many the all-atom model has been used to study capsid inter-
non-enveloped plant viruses, STNV exhibits specific actions with the host cell factors cyclophilin A [119,120]
binding sites for divalent ions, likely calcium, and has and MxB [121], which regulate and restrict HIV-1 viral
been shown experimentally to undergo structural expan- infectivity, respectively.
sion unless these ions are bound. Simulations with and
without bound calcium confirmed that the former main- In a subsequent study, the empty HIV-1 capsid model
tain a smaller diameter and the latter swell. The results of was simulated for 1.2 ms, setting the current published
the work produced an atomistic model for the swollen record for the most substantial all-atom simulation ever
STNV capsid, which was not previously available, as well performed [122 ]. The simulation revealed that the
as an atomistic description of the dynamics underlying capsid translocates chloride across its surface at twice
the swelling process. the rate of sodium through ion-specific channels, which
may relate to the translocation of nucleotides during
The empty poliovirus capsid was studied over a timescale reverse transcription. Further, the capsid exhibited com-
of 200 ns, based on a system of 6 million atoms with plex dynamics, including collective motions that divide
solvent [115]. Simulation results revealed that the capsid the structure into two hemispheres and suggest a mecha-
functions as a semipermeable membrane structure, trans- nism for capsid uncoating, as well as oscillatory surface
locating water molecules, but not ions, in equilibrium waves at four different frequencies that may underlie
across its surface. Further, the solution pressure on the emergent properties of the capsid.
interior of the capsid was found to be negative, owing to
electrostatic interaction of solution electrolytes with the Immature particle lattices
charged capsid surface. The results of the work demon- Retroviruses such as HIV-1, human T-cell leukemia virus
strate that the capsid plays an essential role in maintaining type 1 (HTLV-1), and Rous sarcoma virus (RSV) initially
an environment conducive to the stable accommodation assemble as immature particles from Group-specific anti-
of its RNA genome and associated counterions. gen (Gag) polyproteins. During maturation, proteolytic
processing of Gag yields cleavage products that reassem-
The empty hepatitis B virus (HBV) capsid was simulated ble to produce mature virions [123]. All-atom simulations
for 1.1 ms based on a model of the complete assembly proved invaluable in determining the structures of the
domain, derived from crystallography and molecular immature HTLV-1 [124] and RSV [125] Gag lattices, as
modeling [116 ]. The simulation encompassed 6 million well as the HIV-1 capsid protein-SP1 peptide maturation
atoms with solvent and revealed that the capsid under- intermediate (CA-SP1) [126 ]. Notably, simulations
goes notable asymmetric distortion at equilibrium. Fur- revealed that the CA-SP1 six-helix bundle exists in a
ther, the capsid exhibited a fivefold preference to trans- dynamic helix-coil equilibrium, and that maturation-inhi-
locate sodium over chloride through its triangular pores, biting drugs and mutations act by stabilizing a helical
and induced the localization of sodium along its interior form of the bundle [126 ]. MD studies of CA-SP1 bound
surface. The results of the work implicate the triangular to inositol phosphates showed that these small molecules
pores as the extrusion site of the capsid’s carboxy-termi- facilitate the formation of the six-helix bundle and, thus,
nal domain tails, which contain cellular signals, and promote assembly of the Gag lattice [127 ]. Simulations
suggest a mechanism by which the capsid could modulate of the RSV lattice model were used to determine the
signal exposure based on tail phosphorylation. Simula- effects of charge distribution and mutations on Gag
tions have also been used to investigate the effects of assembly [128].
small-molecule drugs on HBV capsid morphology [107 ]
and to determine the structural basis for enhanced assem- Viral enzymes
bly and drug resistance in HBV capsid mutants [117]. Some viruses encode and package enzymes necessary to
carry out the processes that drive their infection cycles.
An all-atom structure of the human immunodeficiency All-atom MD simulations of the HIV-1 protease
virus type 1 (HIV-1) capsid (Figures 1b and 2 e) was (Figures 1b and 2 b), which is responsible for proteolytic
derived by combining results from cryo-EM and NMR cleavage of Gag prior to maturation, revealed the motion
experiments with computational modeling and data- of the enzyme’s active-site flaps, whose opening and
www.sciencedirect.com Current Opinion in Virology 2018, 31:82–91
86 Virus structure and expression
closing are considered essential to function [129–134]. bacteriophage MS2 [142,143]. The availability of more
Further, studies of the West Nile virus (WNV) NS3 complete structural information, along with improved
protease identified a conformational selection mechanism understanding of genome organization within capsids
used to identify its substrate [135]. Additionally, all-atom [144] and integrative modeling approaches [1 ] that
simulations were instrumental in elucidating the mecha- employ increasingly accurate protein and nucleic acid
nism by which non-nucleoside reverse transcription inhi- force fields [145,146], will support new simulation studies
bitors (NNRTIs), an important class of therapeutics of all-atom virions in the near future, particularly for non-
against HIV-1, interfere with the virus’ reverse transcri- enveloped viruses.
pase [136] (Figures 1b and 2 c), which synthesizes DNA
from the RNA template. All-atom simulations of enveloped viruses will face the
additional challenge of treating the envelope membrane
Toward all-atom simulations of complete lipid bilayer. Due to size, complex lipid compositions, and
virions the inclusion of membrane-embedded surface proteins,
As experimental methods, particularly cryo-EM and cryo- viral envelopes require careful consideration to model and
ET, continue to provide greater detail on virus composi- equilibrate [147]. Further, enclosing a virus capsid in a
tion and architecture, and as supercomputers and simula- fully atomistic envelope will significantly increase system
tion codes continue to offer greater performance for the size and simulation expense, particularly given the inclu-
study of large biological systems, the computational com- sion of solvent. Figure 2 emphasizes the dramatic size
munity becomes poised to study the dynamics of com- disparity between several protein-based components of
plete virions within physiological environments. None- HIV-1 that have been previously investigated with all-
theless, the paucity of accurate, full-length, and fully atom simulations and a model of the intact envelope
atomistic models for some major components of virus membrane (Figure 2f). The envelope necessarily dwarfs
structure presents a significant challenge to the derivation the HIV-1 capsid, the simulations of which currently
and investigation of all-atom virions. represent the most far-reaching accomplishment of
computational virology reported for structures of atomic
Importantly, the lack of accurate all-atom models for detail [118 ,122 ]. Following construction of a complete
encapsidated genome structures is the foremost limiting HIV-1 virion, it is clear that substantial supercomputing
factor for the construction of complete virions. While the power will be required to simulate such a colossal biolog-
work of Freddolino et al. on genome-containing STMV ical assembly at chemical resolution, especially over time-
(Figure 1c) represents the only all-atom simulation of a scales sufficient to allow meaningful study.
complete virion performed to date [108 ], the genome
structure employed was not based on the actual STMV
RNA sequence. Similarly, a complete pariacoto virus Figure 2
(PaV) virion derived using molecular modeling included
an RNA model based on an artificial RNA sequence [137]. (a) (e)
For both of these virions, limitations in determining
genome organization from crystal structures, which typi- (f)
cally rely on icosahedral averaging, led to inaccuracies in
(b)
the resulting RNA models [138,139]. Recently, Zeng et al.
used computational methods to generate the first all-atom
model for the complete structure of any virus using the
(c)
natural genome sequence, that of STMV containing
realistic RNA [5 ].
(d)
Moving forward, modeling and simulation will continue
to play an essential role in the determination of all-atom
structures for genome-containing capsids, particularly
through approaches that integrate experimental data from (g)
techniques such as NMR and cryo-EM [140,141].
20 nm
Although simulation studies of the intact HBV capsid
have shown that the inherent flexibility of some virus
Current Opinion in Virology
structures may limit the ability to obtain true atomic (1–
˚
2 A) resolution with cryo-EM [116 ], advances in image
Graphical size comparison of viral protein components. (a) HIV-1
processing are enabling high-resolution asymmetric
viroporin (Vpu), transmembrane domain. (b) HIV-1 protease. (c) HIV-1
reconstructions capable of producing more authentic
reverse transcriptase (RT). (d) HIV-1 envelope protein (Env)
descriptions of encapsidated genome, such as those ectodomain. (e) HIV-1 capsid. HIV-1 envelope membrane. (g) STMV
obtained for the immature HBV particle and capsid.
Current Opinion in Virology 2018, 31:82–91 www.sciencedirect.com
All-atom simulations of viruses Hadden and Perilla 87
All-atom modeling of STMV with its encapsidated RNA genome, produ-
In the meantime, three viral envelopes have been inves-
cing the first realistic and chemically-complete structure of any virus.
tigated using coarse-grained simulation methods, includ-
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Acknowledgments
14. De Vries R.P., Peng W, Grant OC, Thompson AJ, Zhu X,
This work was supported by the National Institutes of Health grants
Bouwman KM, Torrents de la Pena AT, van Breemen M.J.,
P50GM082251 and P30GM110758-04 and the University of Delaware.
Ambepitiya Wickra-masinghe IN, de Haan C.A.M. et al.: Three
mutations switch H7N9 influenza to human-type receptor
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