Food Chemistry 405 (2023) 134824

Contents lists available at ScienceDirect

Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem

Review

Molecular dynamics simulation of the interaction of food proteins with

small molecules
Xia Hu a, Zhen Zeng a, Jing Zhang a, Di Wu a, *, Hui Li b, Fang Geng a
a
Meat Processing Key Laboratory of Sichuan Province, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
b
School of Chemical Engineering, Sichuan University, Chengdu 610065, China

A R T I C L E I N F O A B S T R A C T

Keywords: Molecular dynamics (MD) simulation is used increasingly to explore mechanisms of interactions and confor­
Molecular dynamics mational relationships between food proteins and other food compounds. MD simulation can better understand
Food protein the structural changes between food proteins and small molecules at the molecular level. Based on the current
Interaction
extensive literature, visualization models established by MD simulation in the future may provide greater insight
Force field
into finer molecular changes in food proteins and small molecules interactions. Development and software as
Prospects
well as force fields used in MD simulation for food protein and interaction systems were reviewed. The review
focuses on the status of MD simulation technology in exploring food protein functional mechanisms, and
bioactive substance delivery, food processing and storage, and food additives. Finally, current trends and ap­
plications were considered. This review provides an overview for the wider application of MD simulation
technology in the food protein research field.

1. Introduction complex food systems with multiple interactions. The combination of

Molecular dynamics (MD) simulation is critical in understanding the
conformational changes and dynamic mechanisms of proteins and is
frequently employed in drug design (Decherchi and Cavalli, 2020).
Through MD simulation, the macroscopic properties of matter can
reflect the microscopic system in time and space through MD simulation.
This technology can simulate various experimental conditions can be
simulated, such as changes in pH, temperature, and solvent. The
controllability of the simulated experimental environment is control­
lable, thereby providing research ideas and options (Al-Khafaji and
Taskin Tok, 2020). At present, MD simulation has been increasingly
applied in research on food protein interaction and is even suitable for
computer simulations and traditional experimental methods is an
inevitable requirement for the development of food science to deepen
the understanding of the interaction mechanisms of food ingredients.
MD simulation technology is based on Newtonian mechanics, which
is an effective technology used to reflect the macroscopic properties of
matter through microscopic systems. Alder and Wainwright’s (Alder &
Wainwright, 1957) first suggested the examination of the mobility of
molecular systems containing 32 to 500 rigid spheres. Computer simu­
lations were applied to protein systems in 1977. McCammon used
bovine trypsin inhibitor for the first realistic simulation of protein dy­
namics (Mccammon, Gelin, & Karplus, 2000). Gillan extended the
method to nonequilibrium systems with temperature gradients in 1983,

Abbreviations: MD, Molecular Dynamics; AMBER, Assisted Model Building with Energy Refinement; CHARMM, Chemistry at HARvard Macromolecular Me­
chanics; GROMACS, GROningen MAchine for Chemical Simulations; GROMOS, GROningen MOlecular Simulation; NAMD, Not just Another Molecular Dynamics;
LAMMPS, Large-scale Atomic/Molecular Massively Parallel Simulator; RedMD, Reduced Molecular Dynamics; YASARA, Yet Another Scientific Artificial Reality
Application; RMSD, Root Mean Square Deviation; RMSF, Root Mean Square Fluctuation; Rg, Radius of Gyration; SASA, Solvent Accessible Surface Area; RDF, Radial
Distribution Function; Hb, Hemoglobin; MPs, Myofibrilla Proteins; AR, Alginate; AO, Alginate Oligosaccharide; PDB, Protein Data Bank; MM-PBSA, Molecular
Mechanics Poisson Boltzmann Surface Area; CnTAB, Chain n-alkyl Trimethylammonium Bromides; 4HBA, 4-hydroxybenzoic Acid; α-LA, Alpha-lactalbumin; β-LG,
β-lactoglobulin; Qy, Quinoline yellow; MolSA, Molecular Surface Area; PSA, Polar Surface Area; ε-PL, ε-polylysine; CAP, Capsaicin; VMD, Visual Molecular Dynamics;
LF, Lactoferrin; apo-LF, Apo-lactoferrin; SL, Sucralose; OVA, Ovalbumin; RES, Resveratrol; FA, Ferulic Acid; DSSP, Define Secondary Structure of Proteins; EGCG,
Epigallocatechin-3-gallate; Ssa, Soyasaponins; HYP, Hyperoside; TMP, Tetramethyl Pyrazine; TIP3P, Transferable Intermolecular Potential with 3-points; hAFP,
herring Antifreeze Protein.
* Corresponding author.
E-mail address: diwulab@163.com (D. Wu).

https://doi.org/10.1016/j.foodchem.2022.134824
Received 27 July 2022; Received in revised form 21 October 2022; Accepted 30 October 2022
Available online 3 November 2022
0308-8146/© 2022 Elsevier Ltd. All rights reserved.
X. Hu et al.
resulting in the use of MD simulation for nonequilibrium systems (Gillan
and Dixon, 2000). MD simulation is used to establish the nutritional
mechanisms of biological macromolecules, materials science, drug
design, and biophysics (Rapaport, 2002). The range of applications of
MD simulation in food proteins is gradually increasing, and its advan­
tages are increasingly known.
Studying the functional properties and structural changes of food
proteins (such as animal-based and plant-based proteins) is of great
significance for new food formulations and processing technologies. MD
simulation has great contributions to further understanding food pro­
teins and their constituent systems. Duan used MD simulation for the
first 1 µs simulation of a protein insolvent and observed the intermediate
pathway of protein folding in 1998 (Duan & Kollman, 1998). In recent
years, the development of MD simulation of food proteins is full of new
possibilities, with advances in protein hydration (Maddah, Maddah, &
Peyvandi, 2021), thermal treatment (Zhao et al., 2022)), and ligand
binding to protein targets (Han et al., 2022). At present, the simulation
of complex systems of proteins is no longer limited by an algorithm but
only by computer power. MD simulation can elucidate complex dynamic
processes in protein systems, such as changes in protein secondary
structure (Wu et al., 2021), stability (Waseem et al., 2022), and binding
energy (S et al., 2022). Results can provide information about fluctua­
tions in target protein: protein backbone fluctuations (Suo et al., 2018),
changes in binding energy between receptor and ligand (Wu et al.,
2021), non-covalent driving forces of system motion (Wu et al., 2022),
root mean square deviation (RMSD) (Vanaei, Parizi, Abdolhosseini, &
Katouzian, 2020), radius of gyration (Rg) (Mohseni-Shahri, Moeinpour,
Malaekeh-Nikouei, & Nassirli, 2017), root mean square fluctuation
(RMSF) (Mohseni-Shahri, Moeinpour, & Nosrati, 2018), solvent acces­
sible surface area (SASA) (Zhao, 2020), radial distribution function
(RDF) (Pan et al., 2021), and interaction energy (Sariyer, Kocer, Danis,
& Turgut-Balik, 2021) of the molecule before and after simulation. The
simulation results can be cross-corroborated with the experimental data.
Changing protein conformation and protein component interactions
caused by processing conditions is a hot topic. Various technologies are
commonly used in the processing of food proteins to improve product
quality or shelf life. Different processing techniques can have different
effects on protein structure and function. Physical or chemical treat­
ments can expand the polypeptide chains or even break them into
smaller fragments, thereby affecting the functional properties of pro­
teins (Amigo and Hernandez-Ledesma, 2020). These significant protein
alterations occur due to protein degradation, protein cross-linking, re­
actions at high temperatures and pressure, and interactions between
proteins and ligands. Application of heat (Mitra, Lametsch, Greco, &
Ruiz-Carrascal, 2018) and high pressure (Mune Mune, Stănciuc,
Grigore-Gurgu, Aprodu, & Borda, 2020) to denature protein molecules
can improve protein digestibility but may induce chemical reactions,
such as Maillard browning. The behavior and structural changes of
proteins throughout processing affect their functional characteristics
and are crucial topics for investigation (Kar, Guha, Subbiah, &
Majumder, 2022). Evaluation at the molecular or even atomic level is
required to understand the interactions between processing conditions
and proteins (Smith, Dong, & Raghavan, 2022). In this regard, MD
simulation has obvious advantages in elucidating molecular mecha­
nisms of protein interactions and is an important tool in research of food
proteins. This work reviews the application and development trend of
MD simulation to investigate interactions among animal-based proteins,
plant-based proteins, and small molecules in food protein research.
2. Molecular dynamics
2.1. Technical principles and algorithms
MD simulation is a computer technology used to analyze the motion
of molecules over time. Samples are taken from a system composed of
different states to calculate the conformational integral (Rapaport,
2
Food Chemistry 405 (2023) 134824
2002). Conformation fraction data are used to determine the thermo­
dynamics and other macroscopic parameters of the system. The force
field describes the interaction of particles, including the functional form
and parameter settings of the system’s potential energy (Adamczyk,
2017; Zheng, Alhossary, Kwoh, & Mu, 2019). This manifests as changes
in system parameters, such as energy, bond length, bond angle, dihedral
angle, flatness, and Coulomb and van der Waals forces (Brooks, 2005).
Therefore, the selection of appropriate software and force field is critical
to simulation.
Various MD simulation software programs are based on different
algorithms, which can be simply understood as treating atoms as clas­
sical particles and solving Newton’s integral equations of motion (Padhi,
Janežič, & Zhang, 2022). The most used numerical solution algorithms
are Verlet algorithm, leap-frog algorithm, Beeman algorithm, and pre­
dictor–corrector method proposed by Gragg. The Verlet algorithm pro­
posed by Verlet (Verlet, 1968) is the simplest and the most widely used
tool in MD simulation. This algorithm has concise execution and low
memory requirement. However, it easily causes precision loss in the
calculation process and is not self-starting, requiring a new location
from the position of the previous instant. Considering the flaws of the
Verlet algorithm, Hockney and his team developed the leap-frog
approach (Hockney, Goel, & Eastwood, 1974). It has good accuracy
and stability and saves memory. This approach can determine velocity
without first calculating the location of the subsequent step; however, it
cannot simultaneously specify the velocity and position. As such, MD
simulation energy and potential energy cannot be defined simulta­
neously, so total energy cannot be calculated directly. Another
commonly used tool is Beeman method (Beeman, 1976). The storage
capacity of this method is greater than that of the Verlet algorithm and
the leap-frog method. It has three to four times longer integration in­
terval and the same accuracy with the Verlet algorithm. Gragg et al.
proposed a predictor–corrector method based on the predictor–corrector
integral (Gragg and Stetter, 1964). The Verlet method can fulfill the
essential criteria for most MD software. This method can generally fulfill
the fundamental needs of MD software, although higher-order algo­
rithms are more practical in several instances. The Gragg algorithm has
good computational accuracy but uses a lot of memory, making it less
useful for simulating many molecular systems than the Verlet algorithm.
MD simulation have many atoms. Many algorithms can solve Newton’s
integral equations of motion and have relatively high requirements on
time and space. Therefore, scholars should determine the integration
algorithm suitable for MD simulation.
2.2. Software and force field
Software is a vehicle used to implement MD simulation. Table 1
shows the computer software programs that are mainly used for MD
simulation. Since the development of software, it has been continuously
updated (Zhou and Liu, 2022). However, different versions of currently
available software vary significantly in terms of running speed and
computing power. In research of food proteins interactions, commonly
used free software programs include GROningen MAchine for Chemical
Simulations (GROMACS) (Schmid, Christ, Christen, Eichenberger, & van
Gunsteren, 2012), Not just Another Molecular Dynamics (NAMD)
(Phillips et al., 2020), Large-scale Atomic/Molecular Massively Parallel
Simulator (LAMMPS) (Thompson, Aktulga, Berger, Bolintineanu,
Brown, & Crozier, 2022), and Reduced Molecular Dynamics (RedMD)
(Gorecki, Szypowski, Dlugosz, & Trylska, 2009). Meanwhile, commer­
cial software programs include Assisted Model Building with Energy
Refinement (AMBER) (Gotz, Clark, & Walker, 2014), Chemistry at
HARvard Macromolecular Mechanics (CHARMM) (Vanommeslaeghe
and Mackerell, 2015), GROningen MOlecular Simulation (GROMOS),
Yet Another Scientific Artificial Reality Application (YASARA) (Krieger
and Vriend, 2014), GAUSSIAN (Chilleri, He, Bedrov, & Kirby, 2021).
GROMACS, NAMD, and LAMMPS are popular open-source software;
they have open access and are free for use, and users can modify the
X. Hu et al. Food Chemistry 405 (2023) 134824

Table 1
List of software for MD simulation.
Software Institution/Region Force field Applicable system License Website

GROMACS (Junghans & University of Groninge CHARMM/ Applicable to biological molecules. Free https://www.gro
Christoph, 2014) G43a1/ macs.org/
GROMOS/
AMBER/OPLS
AMBER (Cornell et al., 1995; University of California AMBER/Glycam Applicable to biological systems including Not free https://ambermd.
Woods and Chappelle, 2000) protein,DNA,RNA,carbohydrates,lipids,organic, org/
molecules (usually ligands).
CHARMM (Bjelkmar, Larsson, Harvard University CHARMM Applicable to biological systems including Not free https://www.ch
Cuendet, Hess, & Lindahl, peptides, proteins, prosthetic groups, small armm.org/
2010; Vanommeslaeghe et al., molecule ligands, nucleic acids, lipids, and
2015) carbohydrates, as they occur in solution, crystals,
and membrane environments.
GROMOS (Schmid et al., 2012) Laboratory of Physical AMBER/ Applicable to alkanes, proteins, and nucleic acids Not free https://www.gr
Chemistry CHARMM/ omos.net/
GROMOS/OPLS-
AA
RedMD (Gorecki et al., 2009) University of Warsaw DL_POLY/ Applicable to proteins, nucleic acids and Free on https://bionano.
NAMD/AMBER/ complexes GPL cent.uw.edu.pl/
CHARMM licence software/redmd/
YASARA(Duan et al., 2020) YASARA Biosciences GmbH;Bio- AMBER/ Applicable to proteins, nucleic acids and other Not free https://www.yasa
Prodict BV;WHAT IF YAMBER/NOVA biological macromolecules. ra.org/
Foundation/CMBI
NAMD (Padua, 2011) Funded by a grant from the AMBER/ Applicable to biomolecular systems. Free https://www.ks.
National Institute of General CHARMM/ uiuc.edu/Research
Medical Sciences of the National Dreiding /namd/
Institutes of Health
LAMMPS (Thompson et al., Sandia National Laboratories LAMMPS Applicable to liquid, solid and gas systems. Free https://www.la
2022) mmps.org/
GAUSSIAN(Lim Chong et al., Goss Corporation AMBER Applicable to inorganic, organic, biological Not free https://gaussian.
2022) molecules, and crystals. com/opt/

source code according to their own needs. GROMACS is mainly used to
simulate many biochemical molecules, such as proteins, lipids, and
nucleic acids, that have complex bonding interactions (Malhotra and
Goyal, 2021). It can simulate the MD of millions of particle systems and
support almost all algorithms; its simulation speed is one to two orders
of magnitude faster than other similar software.
Force field is the basis for MD simulation and calculates the system
energy from atomic positions. It has less calculation time than quantum
mechanical method and can be used to calculate a system containing
tens of thousands of particles (Bin Faheem, Kim, Bae, & Lee, 2021).
Force fields are typically employed to investigate the atomic structure
and characteristics of biological macromolecules to interpret experi­
mental results and provide access to information that is not always
provided by experimental approaches. Several force fields have been
used in studies targeting food proteins, including the GROMOS 54a7
force field in hemoglobin (Hb) with kaempferol (Das et al., 2020), the
AMBER FF14SB force field in β-lactoglobulin with capsaicin (Zhan et al.,
2020) and the CHARMM force field in soy protein with soyasaponins
(Ssa) (Zhao, 2022). In addition, appropriate force field is used for the
corresponding system, leading to more accurate results. For example,
the Amber force field includes several components with different names,
which support different molecular types such as protein, DNA, RNA,
carbohydrate and fat (Case et al., 2005). For systems where only non-
bonded interactions, including electrostatic and van der Waals forces
are considered for food proteins interactions, the AMBER, CHARMM,
GROMOS, OPLS and other Class I force fields can be selected (Singh,
Vanga, Orsat, & Raghavan, 2018). Suppose smaller-scale interactions at
the interatomic level, such as “bond-bond, angle-angle, bond-angle,
bond-both-sides, angle-angle-both-sides, and bond-bond-both-sides” are
to be studied. In that case, secondary and tertiary force fields can be
chosen to achieve higher overall accuracy (Brooks, 2005). Table S1 lists
some common force fields used in MD simulation of food protein
interactions.
2.3. MD simulation of food proteins in GROMACS
GROMACS is published by the Sweden ScalaLife Competence Center
(Lange, Schäfer, & Grubmüller, 2010) and is the most popular program
for protein discovery. GROMACS offers a wide range of tools for tra­
jectory analysis and supports all popular MD simulation technologies
(Brooks, 2005).
MD simulation starts with the determination of molecular structure
parameters. As shown in Fig. 1, protein structures are usually obtained
from the Protein Data Bank (PDB) website (Astrakas, Gousias, & Tza­
phlidou, 2011). Data about small molecules may be found on sites, such
as PubChem (Kim, Jie, Cheng, Gindulyte, & Bolton, 2018) and Chem­
Spider (Williams, 2010). After obtaining the PDB file, the structure can
be processed as needed. The “gmx” or “pdb2gmx” file is used to convert
PDB coordinate files to “topol.top” and force field compatible “conf.gro”
coordinate files. The “topol.top” file allows direct system solvation. The
edit conf command converts “gro” files and “pdb” files. The “conf.gro”
file uses the edit conf command to set up the box for system solvation. In
this method, protein molecules in a periodic cubic lattice are obtained.
The “mdp” files are usually used for energy minimization to generate
“tpr” files and combine coordinate information (gro files) and topolog­
ical information (top files) (Feng et al., 2015). The “cpt” is a breakpoint
file that acts as a position-restricting force on non-hydrogen atoms in the
protein. Once confinement is imposed, these atoms cannot move freely
unless energy is very large so the molecules around the protein will be
balanced without causing changes in the protein structure. The system is
equilibrated at the desired temperature and pressure to release location
constraints and conduct the final MD procedure for data collection. In
general, an MD approach is used to optimize the structure of a simulated
system. After running the simulation program, the data are further
analyzed and processed according to molecular trajectories during the
simulation.
GROMACS is the most used software for MD simulation of biological
systems. It has operating efficiency that is significantly better than
several mainstream similar software programs. GROMACS is preferred
by many users (Abraham et al., 2015) because of its highly optimized

3
X. Hu et al. Food Chemistry 405 (2023) 134824

Fig. 1. A flowchart of MD simulation of a protein in GROMACS.

Fig. 2. The main source of plant-derived protein and animal-derived protein.

4
X. Hu et al.
computing performance and open code. However, food protein com­
ponents are generally complex systems, and researchers need to select
appropriate software to obtain target results.
3. MD simulation in food animal-based and plant-based proteins
Understanding the relationship between protein conformational
changes and function has significantly progressed with the introduction
of MD simulation in research on food protein interactions (Cen et al.,
2022). MD simulation can predict protein interactions as well as ther­
modynamic properties, mechanical properties, and interaction models
under extreme conditions that are difficult to obtain experimentally. It
can also be used in conjunction with experimental methods to corrob­
orate the results (Hu et al., 2022; Wang et al., 2022; Wang et al., 2021).
This review paper presents published literature on the use of MD
simulation to evaluate the interactions of food proteins. According to
source, food proteins are divided into animal-based and plant-based
proteins (Fig. 2). The specific numbers in the figure indicate the pro­
portion of some common types of proteins in food animal-based and
plant-based proteins, respectively (Loveday, 2019; Tomé, 2021). Spe­
cific details will be discussed for different protein classifications and
learning purposes.
3.1. Application of MD simulation in meat proteins
Proteins are one of the most important components of meat and
account for about 20 % of the total composition (Pearson, 1990). Pro­
teins not only have a significant impact on sensory qualities such as
color, flavor, and texture but are also related to the nutritional value of
the meat products. To be functional, proteins should interact with
endogenous or exogenous substances, which may greatly affect their
biological activity. In research on food protein interactions, MD simu­
lation can provide insights different from conventional methods at the
molecular level.
Color is a sensory indicator that directly affects consumers (Faust­
man and Cassens, 1990). The color of meat is mainly determined by
heme proteins, particularly myoglobin and Hb (Bekhit and Faustman,
2005; Pisula, 1975). During meat processing and storage, proteins can
easily combine with oxygen in the air and cause discoloration. However,
glucose can regulate osmotic pressure regulator to stabilize the natural
conformation of myoglobin (Eslami-Farsani, Shareghi, Farhadian, &
Momeni, 2021). In the present study, GROMACS (V 5.1.4) and
CHARMM36 force field were selected for MD simulation of myoglo­
bin–glucose complex and free myoglobin. A rectangular box was used to
contain the myoglobin–glucose complex, which was solvated using the
TIP3 model water molecules. Two Na+ were introduced at random lo­
cations in the simulation to neutralize the solvated system. The simu­
lation results showed a slight decrease in the Rg value, indicating a
change in the conformational tightness of myoglobin. In addition,
glycerol is a polyol that is widely used to stabilize proteins (Feng and
Yan, 2008). The MD trajectories of myoglobin and myoglobin–glycerol
complex was analyzed according to RMSD and Rg values (Eslami-Far­
sani, Shareghi, Farhadian, & Momeni, 2020). The RMSD and Rg values
were constant during myoglobin–glycerol complex binding, the values
of the complexes were smaller than those of myoglobin alone, indicating
a more stable structure of the complexes. And the results of MD analysis
combined with experimental studies on thermal stability showed that
glycerol could enhance the stability of myoglobin. Stabilizing the
conformation brings the possibility of slowing down oxidation and
consequent discoloration, extending the shelf life.
Protein degradation promotes the production of flavor substances
and precursors (Gianelli, Flores, & Toldrá, 2003). The human perception
of flavor depends on the concentration and threshold of volatile com­
pounds; it is also related to the temperature and pressure of volatile
compounds and the interactions among various food ingredients. MD
simulation can be used to characterize proteins that modulate final
5
Food Chemistry 405 (2023) 134824
flavor perception by binding or releasing volatile compounds (Pérez-
Juan, Flores, & Toldrá, 2008). Wang and his co-workers (Wang et al.,
2021) used GROMACS to explore the mechanism underlying heptanal
interaction with myofibrillar proteins (MPs). The RMSD and RMSF
values of the MPs-heptanal system were lower than those of the MPs
system, indicating the stable binding of heptanal to MPs. The results
confirmed the positive effect of aldehyde concentration on the local
microenvironment and structural conformation of MPs and validated
the existence of key interactions between aldehydes and MPs at the
molecular scale. To corroborate simulation and experimental data, re­
searchers can combine MD simulation with experimental techniques,
such as gas chromatography/mass spectrometry (GC/MS), which mea­
sures the amount of volatile chemicals.
During processing and storage, excipients are added to adjust the
structural properties of meat products, such as for gelation, dissolution,
emulsification, viscosity, etc. Liu and his team (Liu et al., 2021) studied
the structural dynamics of myoglobin and sodium chloride by NAMD
2.12 software and Charm 27 force fields. They investigated the struc­
tural changes in myoglobin dissolved in different concentrations of salt
solutions and its stability when combined with digestive enzymes. Salt-
treated myoglobin showed no significant structural changes at lower salt
concentrations, indicating its structural rigidity. When simulations were
performed with 0.4 M sodium chloride for 10 ns, the RMSD values
fluctuated, indicating that the addition of salt disrupted the protein
structural equilibrium. In the simulation, the RMSF of myoglobin fluc­
tuated considerably, showing a dynamic displacement of residues in its
initial position. The results of the simulation combined with experiments
proved that the lower salt concentration would lead to the local
unfolding of the protein chain, thus exposing more hydrophobic groups.
Phenylalanine increases the number of hydrogen bonds with sur­
rounding amino acids, and the structure becomes stable, which de­
creases digestibility.
Polysaccharides are cryoprotective components that can reduce
mechanical damage to meat tissue caused by ice crystals formed during
freezing and storage. In Zhang and his team’s study (Zhang et al., 2020),
Amber 18 software was used for MD simulation and all systems were
solvated by an orthogonal cassette of transferable intermolecular po­
tential with 3-points (TIP3P) water. The myosin atoms were located at
least 1 nm from the edge of the box. Alginate (TR) and alginate oligo­
saccharide (AO) replaced some water molecules on the myosin surface
by electrostatic binding to myosin amino acid residues via hydrogen
bond. This phenomenon reduced the flexibility of the myosin chains and
the risk of protein aggregation, thereby stabilizing the conformational
structure of myosin in the system. The cryoprotected MD simulation and
the myosin homology modeling had similar outcomes.
Oligosaccharides are also used to study the mechanism of the sta­
bilizing effect on shrimp freezing (Zhang et al., 2018). Oligosaccharides
can replace water molecules around the surface of shrimp myosin by
forming hydrogen bonds with polar amino acid residues to stabilize the
protein structure in the absence of water and improve the protein sta­
bility during frozen storage. MD simulation can provide insights into the
mechanism of action at the molecular scale and offer new research di­
rections for food freezing technology. As such, MD simulation can help
explore the regulatory mechanism of auxiliary materials on the quality
of frozen food. Additionally, it offers a theoretical reference to create
additional auxiliary materials with high application value. For example,
the effect of carrageenan oligosaccharides and xylooligosaccharides on
ice-crystal growth in peeled shrimp during frozen storage was explored
(Zhang, Zhang, Shen, and Deng, 2018). The interaction study of herring
antifreeze protein (hAFP) with ice crystals provides an effective method
to reduce mechanical damage to ice crystals (Nian, Cao, & Cai, 2020).
Promote their use in the food industry for shelf life extension and quality
enhancement of frozen goods.
Various meat proteins are used as carriers to deliver active sub­
stances (Chen, Li, & Tang, 2015; Huang & Gong, 2016; Mohammadian,
Salami, Momen, Alavi, & Moosavi-Movahedi, 2018; Ng et al., 2018).
X. Hu et al.
Myoglobin is a crucial transport protein for heart and muscular tissues.
GROMACS was used for MD simulation of myoglobin and
myoglobin–B12 systems, and its analytical tool was employed to analyze
RMSD, number of hydrogen bonds, RMSF, and Rg. The changes in the
number of hydrogen bonds led to the formation of a stable complex with
vitamin B12 that contributed to the efficient delivery of the vitamin in
vivo (Rout et al., 2021a). The molecular mechanics Poisson Boltzmann
surface area (MM-PBSA) indicated that the system stability was favored
by the binding energy of the myoglobin–vitamin B12 system. Hb is an
important blood protein that plays a vital role in the transport of gas
molecules, such as oxygen and carbon dioxide, in the body. MD simu­
lation and CD spectroscopy confirmed the absence of changes in the
secondary structure of Hb in the presence of vitamin B12 (Rout et al.,
2021b). MD simulation can also be used to demonstrate the interaction
between free Hb and isoflavone (Sengupta et al., 2012) and kaempferol
(Das et al., 2020); neither of which induced the unfolding of the Hb
structure. Based on the biological properties of kaempferol and other
flavonoids, their interactions with proteins for the transport of small
molecules and their effects on protein structure should be investigated.
Curcumin exhibits various physiological and pharmacological effects.
YASARA v16.7.22 software and AMBER14 force field revealed the dose
effects of curcumin on the myosin assembly (Zhang et al., 2020). The
RMSF values showed a trend of decreasing or slightly fluctuating, sug­
gesting that curcumin-induced myosin cross-linking caused protein
conformational fluctuations. The interaction interface between proteins
was also analyzed. This work provided new insights into the protein and
curcumin assembly and may contribute to the development of food
ingredient delivery systems.
3.2. Application of MD simulation in milk proteins
Casein is present as supramolecular aggregates in natural milk, and
its fractions include αs1-, αs2-, κ-, and β-casein (Menossi, Cunha, & Braga,
2005). During food processing, casein reacts with other food compo­
nents, leading to changes in food structure and texture. Cao and his co-
workers (Cao et al., 2020) used GROMACS software and AMBER force
field to simulate the binding of αs1-casein to the different alkyl chain n-
alkyl trimethylammonium bromides (CnTAB, n = 10, 12, 14, 16) and
investigated casein interactions induced by different alkyl chains CnTAB
mechanisms. The RMSD and Rg trajectories of C10TAB complexed with
αs1-casein increased significantly within 300 ns, demonstrating that
C10TAB altered the structure of αs1-casein. The accessible hydrophobic
and hydrophilic regions of αs1-casein also increased with the addition of
CnTAB, and polar and hydrophobic interactions occurred when CnTAB
was bound to αs1-casein. The addition of bioactive substances to enhance
the nutritional properties of dairy products is commonly used to develop
functional foods; an example is adding insoluble dietary fiber to dairy
products. β-casein can form covalent compounds with 4-hydroxybenzoic
acid (4HBA) in cereal dietary fiber (Condict, Hung, Ashton, & Kasapis,
2021). The simulation data on the average number of contacts between
4HBA and β-casein residues were analyzed. The average value of amino
acid-ligand contacts within the interatomic cut-off distance of 4.5 Å
suggested that residues 50–56 and 84–94 play the largest role in the
stabilization of 4HBA in this binding pocket. This work broadens the
understanding on the effect of ultra-high temperature sterilization on
bioactive components in dairy systems.
Alpha-lactalbumin (α-LA) and β-lactoglobulin (β-LG) are major whey
proteins in milk; they belong to a class of low-molecular-weight proteins
that can bind and transport small molecules. Nasser et al. (Al-Shabib,
Khan, Malik, Rehman, & Alamery, 2020) investigated the binding of
α-LA and quinoline yellow (Qy) under physiological conditions over
50 ns simulation. The RMSD values of α-LA in the presence and absence
of Qy dye indicated that the α-LA-Qy complex remained constant
throughout the simulation period. Furthermore, the analyses of the
molecular surface area (MolSA), solvent accessible surface area (SASA),
and polar surface area (PSA) of α-LA-Qy complexes showed consistent
6
Food Chemistry 405 (2023) 134824
results over the simulation range, indicating the formation of stable
α-LA-Qy complexes. This work provides comprehensive information on
conformational alterations in biological processes induced by food pig­
ments. GROMACS software and GROMOS96 force field were used to
perform MD simulation of a novel natural food-grade antimicrobial
agent ε-polylysine (ε-PL) and α-LA (Shao, Fang, Li, Chen, & Meng,
2018). The stability of the system was calculated with RMSD during
100 ns MD simulation and reached a steady-state after 40 ns. In addition,
SASA during the binding of ε-PL to α-LA was calculated and had sharp
changes at about 0–40 ns; this finding corresponds to other experimental
reports on the interaction between ε-PL and α-LA.
Capsaicin (CAP) is a well-liked premium condiment. Visual molec­
ular dynamics (VMD) can determine the total number and specific de­
tails of hydrogen bonds formed between CAP and β-LG during
simulation (Humphrey, Dalke, & Schulten, 1996). The hydrogen bond
interactions are not obvious. The binding between β-LG and CAP in­
volves van der Waals interactions. Understanding the interaction
mechanism between β-LG and CAP at the molecular level will improve
the oral bioavailability of CAP and reduce its gastrointestinal irritation.
These findings have important implications for enhancing the concom­
itant effects of biologically active substances (Zhan et al., 2020). β-LG is
used as a carrier for some phenolic compounds and is of great signifi­
cance in the food industry. Kasapis and his group investigated the
interaction of β-LG and vanillic acid at pH 2.4 (Abdollahi, Condict,
Hung, & Kasapis, 2021) and 7.2 (Abdollahi, Condict, Hung, & Kasapis,
2022). The average minimum distance between β-LG and vanillic acid at
pH 7.2 was lower than at pH 2.4. The results demonstrated that pH
significantly affected the binding of β-LG to vanillic acid, and showed
significant differences in the binding of amino acid residues and inter­
action forces. The results provide a theoretical basis for the preservation
of food quality and sensory properties of flavorings and antimicrobial
agents under different acidic conditions. The interaction between β-LG
and lycopene showed a distinct binding behavior under different pH
conditions (Wang et al., 2021). The RMSD value indicated reduced
freedom of movement of the protein and improved stability of the
complex formed at pH 8.1, compared to pH 7.0. The RMSF value indi­
cated that the ligand and protein were relaxed upon binding (Fig. 3B).
The ligands did not significantly alter the protein structure as evidenced
by the small changes in the Rg values. These results provide valuable
information for the development of β-LG based lycopene for functional
food applications.
Lactoferrin (LF) is a multifunctional protein with antibacterial and
iron transport functions (Kris-Etherton, Hecker, Bonanome, Coval, &
Etherton, 2002). During food processing, it is more sensitive to pH and
temperature compared with similar proteins (Sreedhara, Flengsrud,
Langsrud, Kaul, & Vegarud, 2010). Darmawan and his team used the
GROMACS 5.1 and the GROMOS 54A7 force field to investigate the
effect of high (Darmawan, Karagiannis, Hughes, Small, & Hung, 2020)
and low (Darmawan, Karagiannis, Hughes, Small, & Hung, 2021) tem­
peratures on the conformation of apo-lactoferrin (apo-LF) and its
interaction with α-LA and β-LG. Free and bound apo-LF were more stable
at low temperatures, and processing apo-LF with α-LA and β-LG as co-
protectants had greater potential benefits.
β-LG is a good choice for the transport and protection of flavonoids.
MD simulation can be used to determine the quantitative structural af­
finity relationships between β-LG and 28 flavonoids (Geng et al., 2020).
Najmeh Fani and his team (Sattarinezhad et al., 2021) investigated the
interaction between dietary flavonoid daidzein and two types of β-LG.
After about 80 ns, the RMSD and Rg distributions indicated the stabi­
lized complexes of the two types of β-LG with daidzein. However, the
β-LG protein structures bound to daidzein were denser. The changes in
the secondary structure content with time throughout the simulation
were not significant, indicating that the interaction of daidzein with
β-LG did not change the secondary structure of the proteins. In that
paper, all experimental and molecular simulation results support one
another. Both variants of β-LG could be promising daidzein carriers,
X. Hu et al. Food Chemistry 405 (2023) 134824

Fig. 3. Some MD simulation examples. A) RMSF plot for β-LG, and β-LG/LYC complex (1:1) at pH 7.0 and 8.1. (Source: Reproduced with the permission from Wang
et al. (2022). Copyright © 2022, Elsevier) B) RMSFs for free β-LG and β-LG interacting with OLE and SAF. (Source: Reproduced with the permission from Wang et al.
(2021). Copyright © 2021, Elsevier) C) RMSDs of the MD simulation of the free OVA and OVA-TF complex systems. (Source: Reproduced with the permission from
Wu et al. (2020). Copyright © 2020, Elsevier) D) Contact map of Ca atoms of the dimer. E) Contribution of residues to the interaction energy. (Source: Reproduced
with the permission from Ermakova (2021). Copyright © 2021, Elsevier) F) Results of free energy calculations for two complexes. (Source: Reproduced with the
permission from Yu and Liang (2022). Copyright © 2022, Elsevier).

even though one of the β-LG has a little higher affinity for the compound.
3.3. Application of MD simulation in egg proteins
In protein–solvent or co-solvent interactions, protein solubility is an
important factor. MD simulation can obtain detailed information on
protein solvation at different pH values. As a cosolvent, sugar has an
important effect on the structural and functional properties of proteins.
Sucralose (SL) is a sugar substitute in many foods and beverages, and pH
changes and co-solvent addition play an important role in stabilizing the
structure of food proteins. The NAMD2.13 program was used to perform
MD simulation for 25 ns. According to the simulation results, the
accumulation of solvent (there is water) and co-solvent on the oval­
bumin (OVA) surface depended on pH. The OVA structure fluctuated
more under alkaline pH conditions and less under acidic pH conditions,
but no fluctuation was detected at neutral pH. The thermodynamic pa­
rameters and computer simulations confirmed that non-covalent in­
teractions, especially hydrogen bonding and van der Waals interactions,
led to different degrees of OVA denaturation in acidic and basic media
(Agalya, Pires de Oliveira, Lescano, Caires, & Velusamy, 2021).
The combination of pigment components in tea and OVA can affect
the texture and nutrition of the protein, thereby protecting the biological
activity of pigment components in tea. Wu et al. explored the dynamics
behavior of the theaflavin-OVA binding system at pH 7.4 for 40 ns on the
YASARA software (Wu et al., 2020). The binding system was placed in
the center of a box covered by 98 Å × 98 Å × 98 Å along the ×, y, and z
axes, and a solvent environment of 0.9 % NaCl was set. The analysis of
MD traces by RMSD (Fig. 3C), Rg, and secondary structure showed that
the addition of theaflavins led to a more stable OVA structure. MD
simulation was also used to study the interaction of mono-, dis-, and tris-
azo food dyes with egg white lysozyme. According to the structural and
computational analyses, the addition of dyes containing different
numbers of azo groups resulted in different degrees of lysozyme
unfolding. MD simulation can also be used to understand the cluster
analysis and energy contribution of each amino acid residue in protein
interactions. Ermakova and his co-workers (Ermakova, 2021) used MD
simulation to study the primitive fiber fragments of the lysozyme core.
Fig. 3D and E show the contact maps of the dimer atoms and the ener­
getic contribution of each residue to the protein–protein interaction,
respectively.
MD simulation of resveratrol (RES) and OVA were performed using
GROMACS software at constant pressure and temperature (Cheng et al.,
2021). A coupling strategy was used to maintain the temperature at
298 K, and Parrinello–Rahman pressure coupling method was employed
to maintain the pressure at 1 bar. RES combined with Gln-325, Lys-290,
and Gln-162 had the most stable hydrogen bonds, whereas the number
of hydrogen bonds between OVA and RES fluctuated throughout the MD
simulation. Amino acid residues 160–180 and 290–325 are the main
entry points for RES into the OVA active pocket, indicating that small
molecules interact with amino acid residues to create a stable complex.
During the simulation, the shortest path between each amino acid res­
idue of OVA and RES was calculated. These residues contributed to the
stabilization of the intricate structure of OVA and RES. The interactions
between RES and OVA provided a theoretical foundation for the evo­
lution of the latter as a carrier of RES.
Eggs also contain a variety of anti-nutrient proteins, which can
inactivated by heat treatment at 121 ◦ C for 25 min (Yao, Kranthi, Wang,
& Vijaya, 2018). MD simulation can be used to obtain details of the
structural changes in proteins and explain the cause of inactivation.
Wang (Zhu, Wang, et al., 2021) performed MD simulation using GRO­
MACS to observe structural changes in egg avidin after thermal and
electric field pressure treatments. All RMSD and Rg values increased at
300 K because of the loss of the secondary protein structure, leading to
protein unfolding. However, the number of hydrogen bonds in the

7
X. Hu et al.
α-helix structure was significantly reduced, suggesting the reduced sta­
bility of the structure with increasing temperature. When an electric
field was applied, the RMSD value did not significantly change at 333 K
but significant increased at 343 and 353 K compared with than at 300 K.
The increased RMSD value further suggested that variations in the
backbone led to structural modifications and various conformation
mainly due to the rearrangement of hydrogen bonds. The external
electric field significantly affected the number of hydrogen bonds during
the 2 ns simulation. Hence, an oscillating electric field is more useful
than heating to denature/inactivate anti-nutrient proteins. Moreover,
MD simulation under external electric field conditions provides an
important reference for investigating the effects of new food production
technologies, such as microwave and pulsed electric field, on the protein
structure and for optimizing the food production processes.
3.4. Application of MD simulation in plant-based proteins
General consumers and researchers prefer plant-based proteins
because of their lower economic costs and more health benefits than
animal-based proteins. The complexation of proteins from different
plant sources can provide sufficient essential amino acids to meet the
human needs. In plant-based protein interaction and delivery systems,
corn, and soy proteins, which are widely used in the food industry, are
considered good choices.
Zein can self-assemble into different shapes and structures due to its
amphiphilicity and biocompatibility. MD simulation can simulate the
conformational changes of zein in different solvent environments to
evaluate potential applications in polyphenol delivery systems (Reza,
2018). Wang and his team (Wang et al., 2022) used GROMACS software
for 30 ns MD simulation at different concentrations of CaCl2 to study the
conformation of the zein and ferulic acid (FA) complex (Fig. 3A). At
0.1 mol/L CaCl2, FA interacted with Arg-153 via hydrogen bonds;
meanwhile, other amino acid residues Gln-86, Gln-92, Thr-95, Ser-146,
Val-186, Gln-87, Thr-191, and Phe-207 constituted a hydrophobic
pocket that encapsulated FA molecules. The analysis of the dictionary of
the define secondary structure of proteins (DSSP) (Klose, Wallace, &
Janes, 2010) showed a slight increase or decrease in the content of
secondary structures, but the difference was not significant. Yu et al. (Yu
and Liang, 2021) employed MD simulation and chose 3,5-dinitrosali­
cylic acid, which had the lowest pKa value, and trans-ferulic acid,
which had the highest pKa value, to investigate their interaction with
zein. The conformational alterations before and after the MD simulation
indicated the importance of hydrogen bonds and van der Waals forces in
preserving the stable binding of the complexes. The creation of the
hydrogen bond between Tyr-192 and trans-ferulic acid was found to be
the primary interaction that produced fluorescence quenching. The re­
sults on RMSF and MM-PBSA (Fig. 3F) revealed that both phenolic acids
interacted with zein, and the binding free energy of trans-ferulic acid
was larger than that of 3,5-dinitrosalicylic acid. Hence, zein has po­
tential applications in polyphenol delivery systems. Moreover, MD
simulation can be used to visualize the structural conformation of pro­
teins stabilized by biologically active substances. Liu and his group (Liu
et al., 2021) analyzed the zein–epigallocatechin-3-gallate (EGCG)
interaction on AMBER force field and revealed that EGCG has a pro­
pensity to attach the pocket in zein created by residues Try-171, Gln-
174, Leu-176, and Leu-205. Additionally, the equilibrium zein confor­
mations before and after EGCG binding were contradicting. The EGCG-
bound pocket separated the entire protein, and data showed little
changes in the conformation on the right side and a significant change in
the conformation on the left, consistent with the RMSF result. As such,
MD simulation can provide a clear explanation of an experimental
occurrence. The results provide a basis for increasing the possible uses of
plant proteins in nutrition delivery.
Natamycin is a widely used preservative in food, but its water
insolubility limits its application (Thomas, 1976). Zein nanoparticles are
effective nanocarriers for natamycin because they improve its solubility
8
Food Chemistry 405 (2023) 134824
and stability. The zein and natamycin complex helped to facilitate the
encapsulation process. Wu and his team (Wu et al., 2021) used the Verlet
LeapFrog algorithm to study the interaction of natamycin with zein. The
complex was placed in the center of an 8 nm × 8 nm × 8 nm water box,
which was added with Na+ and Cl- ions to balance the charge. Periodic
boundary conditions were applied during 50 ns MD simulation, and the
MD trajectories were examined using GROMACS software. Binding free
energy can indicate whether the system can self-associate and can be
calculated by experimental methods. In this investigation, the binding
free energy of zein and natamycin at 298 K was calculated using MM-
PBSA method. The results are in agree with the free energy deter­
mined by fluorescence studies. In the MD simulation, the protein was
separated into three parts, with residues 1–59, 60–128, and 129–205 in
each region. The RMSF values indicated that the fluctuations in region 1
were more pronounced than those in the other regions, consistent with
the RMSD values. According to the Rg values, region 3 had the largest
motion scale and atomic distance from the center. It also had the largest
accessible area of hydrophilicity and hydrophobicity, which is advan­
tageous for its interaction with natamycin. The simulation also indicated
the number of hydrogen bonds existing between each location and
natamycin. The number of hydrogen bonds gradually increases and the
structure is more stable in region 3 compared to the protein alone.
Soy protein is a widely studied low-cost food component worldwide
(Zhang et al., 2021). β-conglycinin (7S) and glycinin (11S) globulin are
the main stored proteins in soybean protein, which have an important
influence on the structure and functional properties of soybean protein.
Zhao and co-workers (Zhao, 2022) used RMSD values to assess the
structural deviation of ligand-bound protein structures in MD simula­
tion. In addition, the protein structure showed poor stability according
to the CDOCKER_ENERGY results. This result helps to understand the
interaction mechanism between Ssa and 7S/11S. Thus, these formed
complex systems may provide a theoretical basis for future applications
of food surfactants in the food industry. Wu and his group (Wu et al.,
2021) studied the interaction mechanism between hyperoside (HYP)
and 7S/11S. MD simulation of monomer-7S/11S complex and 7S
trimeric/11S oligomeric complex by the YASARA software on AutoDock
VINA program and the RMSD values ranged from 0 to 100 ns. The steady
state was reached at about 20 ns, indicating that HYP was bound stably
to 7S/11S. The RMSD and Rg values after adding HYP indicated that the
structure of 11S was less compact than that of 7S, revealing that the
binding stability and affinity of 7S-HYP were higher than those of 11S-
HYP. The monomeric and multimeric proteins complexed with active
small molecules described here will provide new ideas for construction
of embedding and delivery systems.
Sorghum is commonly used to make liquor, and its main protein is
kafirin. It has long been used as a delivery vehicle in aqueous systems to
encapsulate small bioactive molecules and confer antioxidant activity
(Taylor, Taylor, Belton, & Minnaar, 2009). Ferulic acid (FA) and tetra­
methyl pyrazine (TMP) are two characteristic flavor and bioactive
substances in Baijiu. Zhu et al. performed a 30 ns MD simulation using
GROMACS19.5 software with an Amber99 force field (Zhu, Song, et al.
(2021)). In the first phase of the MD simulation, all the RMSD values for
kafirin increased rapidly; within 25 ns, they all achieved a relative
equilibrium state. As fewer solvent molecules were accessible to reach
the surface during the simulation, the SASA values for α-, β-, and
δ-kafirin decreased. Moreover, the Rg values of α-, β-, and δ-kafirin
decreased. The results combined with the SASA data indicated that the
complexes generated by α-, β-, and δ-kafirin with FA and TMP led to
more compact structures of α-, β-, and δ-kafirin.
4. Prospects and conclusions
Protein research plays an important role in food science and is an
area of increasing interest. Several research papers on “MD simulation of
food proteins” have been published on the ScienceDirect online in the
last decade (Fig. 4). These data suggest that MD simulation technology is
X. Hu et al.
Fig. 4. Number of research papers published in ScienceDirect online on “MD
simulation in food proteins”in the last decade.
increasingly used in the food industry, but it is still in its infancy
compared with that in the pharmaceutical field. The structure of many
food components is unknown, and the current MD simulation technol­
ogy is mainly applied for known molecular structure systems. And
substances whose crystal structures cannot be determined need to be
modeled and therefore have many limitations. Nevertheless, MD simu­
lation has gained increasing attention in food research due to its ad­
vantages of being efficient, intuitive, economical, and fast.
Currently, the development of MD simulation technology in food
protein research is in a phase of rapid development and refinement. For
example, visualizing microstructural changes in food proteins provides
greater insight into the more minute molecular changes occurring in the
food being processed that are not observable to the naked eye. MD
simulation will lay a solid foundation for the analysis of food proteins
and various biological components in the field of food processing and
provide an effective theoretical basis. With the emergence of more
simulation software and algorithms, MD simulation will overcome its
limitations and be applied to more profound and complex food systems.
MD simulation has made tremendous progress in understanding protein
structure and function in food systems, a trend that may develop MD
simulation into a more futuristic technology.
CRediT authorship contribution statement
Xia Hu: Data curation, Investigation, Writing – original draft. Zhen
Zeng: Supervision, Validation, Visualization. Jing Zhang: Data cura­
tion, Formal analysis. Di Wu: Conceptualization, Methodology, Project
administration, Writing – review & editing. Hui Li: Resources, Software.
Fang Geng: Project administration, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
9
Food Chemistry 405 (2023) 134824
Acknowledgment
This work was supported by the National Natural Science Foundation
of China (32072236) and the Applied Basic Research Program of Science
& Technology Department of Sichuan Province.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.foodchem.2022.134824.
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