# Molecular Modeling of Aquaporins and Artificial Transmembrane Channels:
a mini-review and perspective for plants

José Rafael Bordin†, Alexandre Vargas Ilha, Patrick Ruam Bredow Côrtes,
W. Silva-Oliveira, Lucas Avila Pinheiro
Departamento de Física, Instituto de Física e Matemática,
Universidade Federal de Pelotas
Caixa Postal 354, CEP 96001-970, Pelotas, RS, Brazil
<EMAIL_ADDRESS>
Elizane E. de Moraes
Instituto de Física,
Universidade Federal da Bahia
Campus Universitário de Ondina, CEP 40210-340, Salvador, BA, Brazil
Tulio G. Grison, Mateus H. Köhler
Departamento de Física,
Universidade Federal de Santa Maria
Santa Maria, CEP 97105-900, RS, Brazil

###### Abstract

Aquaporins (AQPs) are a family of transmembrane channels that are found from
archaea, eubacteria, and fungi kingdoms to plants and animals. These proteins
play a major role in water and small solutes transport across biological cell
membranes and maintain the osmotic balance of living cells. In this sense,
many works in recent years have been devoted to understanding their behavior,
including in plants, where 5 major groups of AQPs have been identified, whose
physiological function details still have open questions waiting for an
answer. In this direction, we observed in the literature very few Molecular
Modeling studies focusing on plant AQPs. It creates a gap in the proper
depiction of AQPs since Molecular Simulations allow us to get information that
is usually inaccessible by experiments. Likewise, many efforts have been made
to create artificial nanochannels with improved properties. It has the
potential to help humanity (and plants) to face water stress – a current
problem that will be worsened by Climate Change. In this short review, we will
revisit and discuss important computational studies about plant aquaporins and
artificial transmembrane channels. With this, we aim to show how the Molecular
Modeling community can (and should) help to understand plants’ AQPs properties
and function and how we can create new nanotechnology-based artificial
channels.

##  1  A brief introduction to aquaporin transmembrane channels in plants

Ion channels are structures formed when specific proteins are incorporated
into the phospholipid membrane (Hille, 2001). The channels serve to establish
an electrostatic potential gradient across the cell membrane by allowing a
specific flux to pass through the membrane. There are many different ion
channels in living cells. They differ in composition, pore structure, and ion
selectivity (Fu et al., 2000a ). Among the many channels in biological
membranes, the aquaporin (AQP) family of transmembrane proteins selectively
transports water and small solutes across biological cell membranes and
maintains the osmotic balance of living cells. Particularly, plants contain a
large number of AQPs with different selectivity. These channels generally
conduct water, but some additionally conduct physiologically important
molecules such as ammonia (NH3), carbon dioxide (CO2), hydrogen peroxide
(H2O2), and O2 (Törnroth-Horsefield et al., 2006; Ludewig and Dynowski, 2009;
Nyblom et al., 2009; Khandelia et al., 2009; Cordeiro, 2015; Chaumont et al.,
2005; Dynowski et al., 2008a ).

The number of distinct channels in the AQPs is expressive since it is present
in all kingdoms, including archaea, eubacteria, fungi, plants and animal
(Kruse et al., 2006). For vertebrates, there are more than ten AQPs (Salman et
al., 2022), while in plants there are 5 major groups of AQPs: Plasma-Membrane
Intrinsic proteins (PIPs), Tonoplast Intrinsic Proteins (TIPs), Nodulin-26
like Intrinsic Proteins ( NIPs), Small Basic Intrinsic Proteins (SIPs) and
X-intrinsic proteins (XIPs) (Kruse et al., 2006; Kaldenhoff and Fischer, 2006;
Fox et al., 2017; Vajpai et al., 2018). PIPs and TIPs contribute to
intracellular water balance and transcellular water flow (Maurel et al.,
2008). AQPs located in the plasma membrane, the PIPs, are mainly located in
organs characterized by large fluxes of water, such as vascular tissues, guard
cells, and flowers Kapilan et al., 2018. However, they are usually subdivided
into two subgroups, PIP1 and PIP2, such that the morphology and physiological
functions of the organs where the proteins are present can be completely
distinct regarding to water or CO2 transport (Kaldenhoff and Fischer, 2006).
TIPs are also permeable to small solutes such as urea, ammonia, and hydrogen
peroxide (Dynowski et al., 2008a ; Mao and Sun, 2015). NIPs were initially
found in the peribacteroid membrane of legume symbiotic root nodules – nodulin
proteins are expressed by plants and transferred to the membranes during the
formation of the nodules (Fortin et al., 1985). They are permeable to numerous
small molecules, including both beneficial and toxic metalloids, but usually
have small water permeability (Lopez et al., 2012). SIPs are not well
characterized, and their physiological functions are not clear (Ishikawa et
al., 2005), while XIPs are permeable to various solutes but only moderately to
water (Lopez et al., 2013), being evolved in osmotic regulation, H2O2
transport and metal homeostasis (Noronha et al., 2016) and have been
characterized in protozoa, fungi, mosses, and dicots (Park et al., 2010).

Sure, the role and even the type of AQPs depends on the location in the plant
(Ding et al., 2019), with AQPs being crucial for water and CO2 transport.
Despite that a higher water transport rate is observed inside PIP channels,
there is evidence of CO2 permeable AQPs in leaves in mesophyll cells and
stomatal guard cells (Terashima and Ono, 2002; Groszmann et al., 2017). Also,
plants counteract variations in water supply by regulating all AQPs in the
cell (Törnroth-Horsefield et al., 2006). In this sense, experimental results
indicate that PIPs are responsible for the water transport in Arabidopsis
under hydric stress (Martre et al., 2002) and to control the hydrogen peroxide
$(H_{2}O_{2})$ transport into plant roots (Israel et al., 2022). Also, AQPs
are evolved in the roots branching patterns in heterogeneous soil water
conditions. Recently, the water flux was linked with a dynamic hormone
redistribution: by closing the pores the ability of the hormone auxin to
initiate lateral root development in dry soil is blocked (Mehra et al., 2022).
Also, PIPs regulate water transfer from the stigma to pollen in the early
events of pollination in the crucifer family (Ikeda et al., 1997).

Recent work on plants in the situation of oxygen deficiency, the so-called
hypoxi, indicates a compensatory mechanism that increases the ability of AQPs
to conduct water to compensate for the decline in hydraulic conductivity
(Kudoyarova et al., 2022). Organs responsible for the mechanical movement of
the leaf and for the leaf hydraulic conductance also have AQPs in a key role
(Moshelion et al., 2002; Lopez et al., 2013). Studies in the area of hydraulic
resistance have a direct impact once water stress usually leads to damage to
the crop, directly impacting plant life and crop yield, and recent findings
indicate the importance of understanding AQPs to improve plantation
productivity in the face of adverse situations (Ahmed et al., 2021). O The
identification of AQPs in different tissues (Sakurai et al., 2008), the
response behavior of the plant to environmental stresses (Kapilan et al.,
2018; Yu et al., 2006) in addition to the crucial process of plant flowering
(Li et al., 2022b ) among other processes have currently been reported. One of
the other several examples to be cited is about reproduction, this process in
plants is related to the movement of water between cells or tissues, which
action has already been observed in relationships with AQPs (Bots et al.,
2005).

Therefore, due to its importance and relevance, a great effort has been made
to understand the structure and water conduction and selectivity mechanisms of
AQPs in the last decades (Fu et al., 2000b ; Murata et al., 2000; Sui et al.,
2001; de Groot and Grubmuller, 2001; Tajkhorshid et al., 2002; Tournaire-Roux
et al., 2003; Hub and De Groot, 2008; Verdoucq et al., 2008; Fischer and
Kaldenhoff, 2008; Dynowski et al., 2008b ; Aponte-Santamaría et al., 2010; Qiu
et al., 2010; Nyblom et al., 2009; Neto and Cordeiro, 2016; Törnroth-
Horsefield et al., 2006; Ludewig and Dynowski, 2009; Khandelia et al., 2009;
Cordeiro, 2015; Chaumont et al., 2005; Dynowski et al., 2008a ; Wang et al.,
2021b ; Hadidi et al., 2021; Maroli and Kolandaivel, 2020; Yadav et al., 2020;
Hadidi et al., 2022; Hub and de Groot, 2006; Mangiatordi et al., 2016; Zwiazek
et al., 2017). Unfortunately, due to the insensitivity of existing
experimental methods such as X-ray crystallography or NMR spectroscopy to the
relatively short timeframes (in the range of nanoseconds) of water conduction
events, this aim remains largely unfulfilled. In addition, experiments at the
molecular level cannot explain how water organize diffuses, and flux in a
confined situation. In this context, simulations computational, the front-line
approach for modeling the behavior of bio-macromolecules at the molecular
level, has played an unprecedented role (Mangiatordi et al., 2016). Among the
many possibilities that computer simulations bring, the creation of artificial
nanoscience-based pores is possibly one of the most exciting.

Despite the relevance, there are few simulational works focusing on plant AQPs
or in using Molecular Simulation to design new artificial nanopores to mimic,
and even overcome, plants AQPs properties. In the next sections, we summarize
the recent findings on Molecular Dynamics (MD) simulations of AQPs and water
flow inside synthetic transmembrane channels. Next, we discuss some
perspectives in this research field and how Molecular Simulations can play a
significant role to increase our understanding of plant Aquaporins and lead to
new technologies.

##  2 Molecular dynamics simulations on aquaporins

Molecular Simulations have emerged as a powerful tool to study the physical
behavior of fluids by modeling the motion and interactions of atoms and
molecules. Classical MD simulations lie in a computational technique that uses
Newton’s laws of motion to predict the position and momentum space
trajectories of a system of classical particles. Therefore, it is necessary to
inform the intermolecular potential of particles, which are used to calculate
potential energies and forces, and thus obtain the thermodynamic, transport,
and structural properties of the system. This potential function accounts for
all the atomic interactions, such as stretching, bending, torsional
interactions, van der Waals forces, and long-range electrostatic Coulomb
interactions.

An important advantage of MD is to accurately describe the complex structure
of AQPs, and model the collective behavior of water in this complex structure.
First, water is a complex substance to model, because of the competing effects
of hydrogen bonding and van der Waals interactions. In addition, the structure
AQPs exist as tetrameric assemblies in which monomers act as independent water
channels. Each monomer is formed by six tilted transmembrane helices (H1-H6),
two short helices (HB and HE), and five interconnecting loops (LA-LE). Two
characteristic domains regulate water permeation through AQPs (de Groot and
Grubmuller, 2001; Hashido et al., 2005; Qiu et al., 2010; Cordeiro, 2015). One
domain has two highly conserved Asn-Pro-Ala (NPA) motifs, which are held
together in the middle of the membrane layer at the two short helices, HB and
HE. This pathway consists of a 2nm-long pore that connects the cytoplasmic and
extracellular vestibules of the protein. The formation of a narrow water file
is assisted by a series of backbone carbonyl groups and hydrophilic side
chains placed along the pore. At the pore center, two highly conserved NPA
motifs provide selectivity against the passage of H+ and other ions. Close to
the extracellular exit of the channel, the so-called aromatic/arginine (ar/R)
constriction region also contributes to selectivity. Some AQPs are permeated
not only by water, but also by gasses, ions, glycerol, and other small
molecules. There is a difference in the structure between mammalian and plant
AQPs. In mammals, the formation of the tetrameric complex is driven solely by
van der Waals interactions between the monomeric subunits. Thus mammalian AQPs
are constitutively open channels and transport water whenever under osmotic
stress. In the case of plants AQPs, monomers are held together by disulfide
bonds between conserved cysteine residues at the extracellular loops LA
forming are gated channels that can be regulated by various mechanisms
(Törnroth-Horsefield et al., 2006; Nyblom et al., 2009), for example,
regulating the phosphorylation of specific serine residues (Törnroth-
Horsefield et al., 2006; Ludewig and Dynowski, 2009; Cordeiro, 2015). In the
closed, unphosphorylated state, loop LD caps the cytoplasmic exit of the
channel and blocks water passage. In this context, the water transport through
AQPs across plant cells is regulated by gating mechanisms. Therefore,
obtaining the crystal structure plant AQP is very complex. On the basis of
these atomic structures, MD simulations have been widely employed to
investigate water dynamics in AQPs, and have provided new insights into the
mechanism of permeation and selectivity of AQPs (Fu et al., 2000b ; Murata et
al., 2000; Sui et al., 2001; de Groot and Grubmuller, 2001; Tajkhorshid et
al., 2002; Tournaire-Roux et al., 2003; Hashido et al., 2005; Hub and De
Groot, 2008; Verdoucq et al., 2008; Fischer and Kaldenhoff, 2008; Dynowski et
al., 2008b ; Aponte-Santamaría et al., 2010; Qiu et al., 2010; Törnroth-
Horsefield et al., 2006; Ludewig and Dynowski, 2009; Hub et al., 2009;
Khandelia et al., 2009; Cordeiro, 2015; Alishahi and Kamali, 2018, 2019;
Gravelle et al., 2014; Hadidi et al., 2022; Hall et al., 2019; Hub and de
Groot, 2006; AlJensen MØ, 2006; Jensen et al., 2008; Lohrasebi and Koslowski,
2019; Mangiatordi et al., 2016; Neumann et al., 2020; Ozu et al., 2013; Roux
and Schulten, 2004; Wambo et al., 2017; Wang and Tajkhorshid, 2007; Zhu et
al., 2004).

###  2.1 Molecular mechanisms of water transport

The description at atomic resolution via MD of how water and solutes are
transported in AQPS has been derived from landmark structural studies on the
microbial and animal prototypes, GlpF and AQP-1 (Fu et al., 2000b ; Murata et
al., 2000; Sui et al., 2001; de Groot and Grubmuller, 2001; Tajkhorshid et
al., 2002; Tournaire-Roux et al., 2003; Hashido et al., 2005; Hub and De
Groot, 2008; Verdoucq et al., 2008; Fischer and Kaldenhoff, 2008; Dynowski et
al., 2008b ; Aponte-Santamaría et al., 2010; Qiu et al., 2010; Cordeiro,
2015). The pioneering work of Groot e Grubmüller (de Groot and Grubmuller,
2001) described the mechanism of water permeation through the pore of an AQPS.
The selectivity of this pore is established by a two-stage filter. The first
stage of the filter is located in the central part of the channel at the NPA
motifs located at the first intracellular and the third extracellular loop.
Both loops are hydrophobic and dip into the membrane lining the NPA boxes
directly on top of each other forming the selectivity region. The second stage
is located on the extracellular face of the channel in the aromatic/arginine
(ar/R) constriction region and operates as a filter that blocks the passage of
protons and other cations. These hydrophobic regions near the NPA motifs are
rate-limiting water barriers and reduce interactions between water molecules
(hydrogen bonds). These authors showed that water permeates in a single-file
arrangement and that a fine-tuned water dipole rotation during passage is
essential for water selectivity (de Groot and Grubmuller, 2001). The alignment
pattern was attributed to the electric fields arising from the macrodipoles of
the two half helices HB and HE (de Groot and Grubmuller, 2001).

Törnroth-Horsefield et al. (Törnroth-Horsefield et al., 2006) reported seven
water molecules in the spinach leaf SoPIP2;1 protein channel via MD. The
structure reveals that SoPIP2;1 is not a constitutively open channel and its
conformation fluctuates between closed and open states depending on the
conformation of a 20-residue cytoplasmic loop, the D-loop (Törnroth-Horsefield
et al., 2006). The authors observed the phosphorylation of the serine residues
favors the open conformation of the channel, therefore, the realization of
water transport. During the simulations, this configuration exhibited a highly
correlated motion along the pore axis. In addition, a specific orientation of
water molecules across the NPA motif is observed indicating the presence of a
positive electrostatic potential at the NPA region to prevent proton
translocation in AQPs, as reported in of Groot e Grubmüller (de Groot and
Grubmuller, 2001). Later, Khandelia et al. (Khandelia et al., 2009),
investigated via MD the possibility of driving the conformations equilibrium
of the SoPIP2;1 protein channel toward a constitutive open state, introducing
two separate mutations in the D-loop while being in the closed conformation.
The simulations suggest the permeability of the open conformation of SoPIP2;1
permeability of the open conformation $1.42x10^{-14}$ cm${}^{3}/s$.

Cordeiro (Cordeiro, 2015) calculated via MD the distribution and organization
of water molecules in AQP1 and plant PIP2;1 (Spinacia oleracia plasma membrane
intrinsic protein) channels using interatomic interactions described with the
GROMOS 54A7 force field for AQPS, and SPC water model (Cordeiro, 2015). Inside
the pore, water molecules were organized as a narrow file. Their dipoles were
oriented according to the electrostatic macrodipoles generated by helices HB
and HE (Fig. 1a-c). Water dipoles in different halves of the channel were
oppositely oriented, meaning that molecules were forced to reorient as they
passed through the NPA region. The average coordination number to other water
molecules had values between 1 and 2 due to occasional disruptions in the
water file structure (Fig. 1d). In the case of AQP1, disruptions were more
significant at the ar/R constriction region. The motion of water molecules
close to the NPA region was highly correlated, indicating that molecules moved
collectively along the pore (Fig. 1e)(Cordeiro, 2015).

The permeability of AQPs is based on the collective motion of water molecules
along the pore. The quantitative values of water permeability, $P{{}_{f}}$,
for the single channel osmotic permeability of mammalian AQP-1 around 3.6
(Cordeiro, 2015) 7.1 (Zhu et al., 2004), 10.3 (Hashido et al., 2007) and
$7.5x10^{-14}$ cm${}^{3}/s$ (de Groot and Grubmuller, 2001). These works
showed excellent agreement with the experimentally determined 5.4 x 10-14
cm3/s (Engel and Stahlberg, 2002). In the case of AQP-0 (the membrane protein
of the lens fiber cells) transports water more slowly than other AQPs such as
AQP-1. In the literature were reported $P{{}_{f}}$ of AQP-0 based on MD
simulations are 0.2 (Hashido et al., 2005, 2007) and 0.28 x 10-14 cm${}^{3}/s$
)Jensen et al., 2008) , while reported experimental value is 0.25 x 10-14
cm${}^{3}/s$ (Qiu et al., 2010). In the AqpZ and Glpf was related $P{{}_{f}}$
around 16-14 cm${}^{3}/s$ (Hashido et al., 2007) The AQPs showed a wide range
of $P{{}_{f}}$ values due that differences in the channel structures would
determine the $P{{}_{f}}$ values.

###  2.2 Molecular mechanisms of physiologically molecules transport

The physiological function of AQPs in conducting gas molecules is not fully
known (Alishahi and Kamali, 2019). MD modeling identified that there are
possible routes for CO2 to cross in a membrane (Wang et al., 2007). In
addition, AQPs are capable of transporting ROS across phospholipid membranes.
MD simulations (Cordeiro, 2015), showed that water and ROS had similar
transport features and $H_{2}O_{2}$ might be transported by mammalian and
plant AQPs. In addition, recent work (Alishahi and Kamali, 2019) has shown
that CO2 molecules may pass through all AQP-5 monomer channels, such as the
central pore. The core pore of AQP-5, like other AQPs, is known to be
impervious to water molecules (Janosi and Ceccarelli, 2013). CO2 molecules,
unlike water molecules, may readily pass through the AQP-5 central pore. The
hydrophobic property of AQP’s central pore has no influence on the passage of
nonpolar CO2 molecules across this channel (Alishahi and Kamali, 2019). A
number of CO2 molecules diffuse through the palmitoyloleyl
phosphatidylethanolamine (POPE) bilayer due to the free volume in the lipid
structure. The greatest energy barrier for CO2 molecules in the channel for a
specific CO2 diffusion with velocity 1 Å/ns is 8.8kcal/mol, but the energy
barrier of the central pore does not surpass 5.1Kcal/mol for the same
simulation Alishahi and Kamali, 2019. As a result, the hydrophobic central
pore is the best route for CO2 molecules to pass through the AQP5 (Alishahi
and Kamali, 2019).

Despite the MD simulations to quantitatively reproduce experimental
parameters, even when different force field parameters and conditions were
used. On the other hand, MD neglects the quantum mechanical effects of the
systems. Therefore, it is impossible to consider the effects of chemical bond
formation and breakage, and consequently, it was not possible to obtain proton
diffusion. Furthermore, the literature lacks a greater discussion of
theoretical and experimental work on water transport in open channels of AQPs
plants. This is attributed to the great difficulty in obtaining the structure
of these plants.

###  2.3 H+ exclusion by aquaporins

The plants AQPs membrane channels as their opening and closing gating is
regulated by multiple effectors including H+, phosphorylation, and others.
Since the determination of X-ray structures of spinach SoPIP2;1 in an open
pore and a closed pore conformation, and MD of water transport in the open
pore (Törnroth-Horsefield et al., 2006; Khandelia et al., 2009). However,the
effect of phosphorylation on AQPS should be further explored in simulations.
In addition, there is no experimental evidence of the efficient transport of
H+ that any plant AQPs has, until the moment. In simulations of AQP-1 (De
Groot et al., 2003; Burykin and Warshel, 2003; Chakrabarti et al., 2004; Kato
et al., 2006), showed the large electrostatic barrier impeded H+ flux,
together with the dehydration cost of moving a proton into the narrow
hydrophobic channel. The electrostatic barrier excluded protons from
permeating even in the presence of an intact proton wire (Chen et al., 2006;
Kato et al., 2006; Hub et al., 2009).

##  3 Computational studies on water flow in synthetic ionic nanochannels and
membranes

Artificial nanochannels mimicking water transport of organic membranes have
been extensively investigated in the last few decades. AQP analogs are
expected to help materials science and nanofluidics to establish a new era for
desalination and water purification technologies (Kocsis et al., 2018). It
also means that we now have access to what extent the charge distribution,
atomic arrangement, and molecular architecture are determinants for the water
conduction within our very cells. There is no surprise that so many condensed
matter groups worldwide are now focusing efforts on investigating the
interaction at solid-liquid interfaces of solid state-based nanochannels and
membranes. These artificial membranes open several new potential advantages,
such as improved stability, simple and scalable fabrication, and controlled
functionalization (Kolahalam et al., 2019; Baig et al., 2021; Speranza, 2021;
Leão et al., 2023) – and no toxicity (da Rosa et al., 2021).

The research on synthetic aquaporin-like nanopores is focused mainly on the
design and synthesis of novel conducting channels with improved water
transport performances and solute rejection properties. It is important to
note that a possible knowledge gap between solid-state nanochannels and
naturally occurring AQPs lies in the enhanced dielectric exclusion due to the
cylindrical shape of most of the artificial nanochannels being studied today
(Yaroshchuk, 2000). In fact, ionic rejection is very sensitive to these
factors (Bordin et al., 2012).

Computational simulations based on classical MD or first-principles DFT have
been vastly employed to decipher the details regarding water conduction in
nanochannels composed of different atomic arrangements. Most recently, some
groups started using artificial intelligence based on graph neural networks to
enhance the search for new, improved materials to be used in desalination
plants (Wang et al., 2021a ). Porosity and adsorption properties are also
being studied with the assistance of machine and deep learning (Jian et al.,
2022; Ogoke et al., 2022).

###  3.1 Water structure under subnanometer confinement

The confinement of water in nanochannels (e.g., nanotubes and 2D materials) is
able to freeze water into crystalline ice-like solids, and it can happen at
ambient pressure and temperature conditions (Köhler et al., 2017; Corti et
al., 2021). Koga et al. (Koga et al., 2000) found ice structures inside carbon
nanotubes (CNTs) characterized as stacked, ordered polygonal rings of water
molecules. Further analysis of ice structures suggests the existence of many
ice phases inside nanotubes (Takaiwa et al., 2008). Over the past decades, a
vast ensemble of structures has been found inside these nanotubes, making them
a prominent tool for exploring water anomalies. The number, shape, and other
structural properties of the confined water are extremely dependent on the
size of the nanochannels.

Highly permeable water channels based on CNTs are at the forefront of
translocation and separation studies. Inside their smooth structure, water
behaves differently. It performs disruptive dynamics, freezing, and even
multi-phases (Kotsalis et al., 2004; Bordin et al., 2014). Recently, Farimani
and Aluru (Barati Farimani and Aluru, 2016) showed the existence of multiple
phases of water at CNTs under atmospheric conditions. They found vapor, high-
density ice, and liquid water phases to coexist in the region within 1 nm from
the surface of the nanotube. These results can explain, for example, the no-
slip phenomena (Secchi et al., 2016) and the fast transport of water in
bundles of CNTs (Majumder et al., 2005).

###  3.2 Water flux in synthetic nanochannels

The inner walls of a CNT are known for being electrically and mechanically
smooth. It allows for the formation of a depletion layer at the interface that
results in high water flux (Köhler and Bordin, 2018). However, the smooth
inner surface contrasts with often abrupt entrances. The problem at a usual
entrance of a CNT is that much of the energy that would be converted in a
highly organized stream flow is lost through friction due to collisions of
water molecules and carbon atoms. Interestingly, nanotubes built from carbon
atoms assembled in an AQP architecture (conical entrances with varying opening
angles, see Figure 2) exhibited increased water permeability as compared to
pristine CNTs, as shown in a theoretical study by Gravelle et al. (Gravelle et
al., 2013). It suggests that the hourglass shape present in a significant
number of AQPs may be the result of a natural selection process toward optimal
permeability. The same group further combined MD simulations with finite
element (FE) calculations to explore the implications of friction and energy
dissipation at the nanopore/reservoir interface (Gravelle et al., 2014). All
to confirm that the hourglass shape inspired in AQPs enhances the water
transportation efficiency down to a single-file regime, with a maximum at
shallow opening angles of around 5º. This illustrates the importance of
entrance dissipation in nanofluidic systems and stresses how the fine-tuning
of the nanopore geometry is necessary for optimizing water transport. More
recently, inspired by the work of Gravelle’s group, Hadidi and Kamali (Hadidi
and Kamali, 2020) have shown that an external pressure difference can lead to
a water flux enhancement. A similar enhancement is observed when an external
electric field is applied. The high flux regimes can be explained in terms of
a reduction in the steric crowding effect of water molecules and an increase
in the average number of hydrogen bonds, both occurring at the entrance of the
nanochannel.

Aquaporins’ capacity for mediating highly selective and fast water transport
has also inspired the advance and development of different supramolecular ion-
excluding artificial water channels. In a recent contribution, Roy et al. (Roy
et al., 2021) studied different types of foldamer-derived polymer-based
synthetic water channels to find that tuning of interior groups and attachment
of carboxylic acid-based lipid anchors lead them to an outstanding transport
of about $2.7\times 10^{10}$ water molecules per second. They also found these
membranes to possess a high capacity to reject both salts and protons.

###  3.3 Nanopore selectivity

The specificities of the nanopore architecture play a huge role in preventing
or accelerating ionic passage. Many computational studies have been employed
to understand this topic using artificial Bio-inspired nanopores. Bordin and
co-authores have conducted simulations using a cylinder made by annular rings
of Lennard-Jones spheres as the ionic channel (Bordin et al., 2012), the
dielectric constant of water equals to bulk water value, K+ ions with several
concentrations, so they could compare their results with experiments of
gramicidin A (gA). The binding sites and the selectivity in the artificial
channel were obtained by inserting negative charges in two specific points of
the hydrophobic nanotube structure - similar to a functionalized carbon
nanotube. They found a similar current versus voltage behavior between
simulations and experiments. The resemblance was verified to different
concentrations.

Among the computational alternatives available to investigate ionic transport
and rejection in nanochannels, Brownian Dynamics (BD) is currently one of the
most suitable tools because of its integration scheme that involves only the
ionic motion. At the same time, the degrees of freedom of proteins and other
bodies are kept fixed. In this method, the water is modeled as a continuum
external field with a proper dielectric constant assumed (Carr et al., 2011;
Bordin et al., 2016).

Many computational studies have employed CNTs to mimic organic ion channels
for ion selectivity. For example, AQPs and other biological systems need
selectivity between cations and anions for processes of organelle
acidification or maintaining an electrochemical gradient across cells (Hille,
1978; Wang and Tajkhorshid, 2007; Warshel, 2005).

A typical ionic exclusion and selectivity prototype involves a nanochannel
small enough to offer a natural mechanical barrier (Köhler et al., 2019; Abal
et al., 2020). Since strongly hydrated ions prefer to stay that way
(preserving their electrostatic configuration), the efficiency of the membrane
will depend on the hydration level (Thomas et al., 2014). Hydrated ions have
their passage facilitated in larger pores due to an energetic penalty
associated with the unbinding of water molecules from de solvation shell.
However, the passage of those ions through smaller nanopores is completely
hindered since they have to dissociate from water. This mechanism explains why
synthetic bio-inspired membranes with nanochannels can efficiently prevent the
passage of ions while allowing for unimpeded water transport.

##  4 Conclusions and Perspectives

Despite its relevance, there is a clear lack of Molecular Simulation works
devoted to unraveling the details of the AQP channel’s function in plants. The
filling of this gap could greatly increase our understanding of the permeation
of distinct molecules, such as water, CO2, H2O2, ammonia, and urea, in PIPs
and TIPs, and even shade some light in the SIPs physiological functions.
Beyond that, we face a period in history where climate changes are
accelerating extreme weather events, such as long periods of drought or
violent storms. Plants will have to adapt or their very existence will be
threatened (Pörtner et al., 2022).

Nanotechnology and nanoscience have a central role in this urgent demand. Many
studies indicate that we can insert artificial nanopores with specific
functions into cellular membranes (Höfinger et al., 2011; Dutt et al., 2011;
Baoukina et al., 2013; Thomas et al., 2015; Geng et al., 2014; Kanno et al.,
2022; Wang et al., 2022a ). Then, if they can mimic the behavior of distinct
transmembrane channels, why can we not improve their performance? Recent
advances in nanotube functionalization uncovered new possibilities (Hirsch,
2002; Bordin and Barbosa, 2017; Kharlamova et al., 2022; Hosseini and
Ghaffarzadeh, 2022; Pardehkhorram and Andrieu-Brunsen, 2022; Li et al., 2022a
; Xu et al., 2022; Turhan et al., 2022).

Now, we can use them to control, for instance, the water permeation into plant
roots under water stress by using artificial channels with distinct
functionalization. We can increase or decrease the permeation to specific
molecules in roots and leaves, including releasing fertilizers and nutrients
at a fixed, well-defined rate (Yanovska et al., 2021; Vakal et al., 2022).
Even the pesticide delivery can be controlled (Singh et al., 2022; Wang et
al., 2022b ; Bhattacharya et al., 2022), minimizing the health and
environmental damages associated with the misuse of pesticides (Li and Fantke,
2022; Cara et al., 2022; Tudi et al., 2022).

Finally, we address the fact that Molecular Modeling is a powerful tool to
design nanomaterials with specific functions, providing insights that are
often inaccessible in experiments. This mini-review and perspective aimed to
show how urgent it is to increase the collaboration between Molecular
Simulations and Plant Physiology communities, filling the gaps and increasing
our understanding of molecular details of the plant machinery, and proposing
ways to help to overcome the current and next challenges that plants will
face, mainly due the Climate Changes.

## Acknowledgments

JRB is grateful to Gustavo M, Souza for the invitation to submit this
minireview and pescpective, and for the stimulating discussions about Biology,
Physics, Life and everything else.

Without public funding, this research would be impossible. JRB is grateful to
the Brazilian National Council for Scientific and Technological Development
(CNPq), PQ Grant nr. 304958/2022-0, and Research Support Foundation of the
State of Rio Grande do Sul (FAPERGS), PqG Grant n2. 21/2551-0002024-5, for
funding support. MHK and JRB thanks CNPq Universal grant nr. 306709/2021-0.
MHK thanks FAPERGS PqG Grant nr. 21/2551-0002023-7. LAP and TG thank CNPq and
AVI, PRBC, and WSO thank the Coordination for the Improvement of Higher
Education Personnel (CAPES, financing Code 001) for the Scholarship.

## Declarations

The authors disclose no conflicts of interest. All authors contribute equally
to this paper.

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Figure 1: (a) Distribution of water molecules along the pores of AQP1 (full
black) and PIP2;1 (dotted red). The positions of the NPA and ar/R regions are
represented in the background. (b) Simulation snapshot showing water molecules
(van der Waals spheres) in the AQP1 channel (transparent grey). Helices HB and
HE are highlighted in cyan with their macrodipoles as black arrows. The Asn
residues at the NPA region are shown in licorice representation. (c)
Orientation of water dipoles expressed as function of their angle with respect
to the z-axis. (d) Coordination of water to other water molecules. (e)
Correlation coefficient c(z) related to the motion of adjacent water molecules
along the pore. Adapted with permission from Cordeiro, 2015. Figure 2: (a)
Schematic Finite Elements (FE) cylindrical and hourglass geometries and (b)
the corresponding DM simulation setups. Adapted with permission from Gravelle
et al., 2014.