Steered Molecular Dynamics Simulations Research Articles

Mechanical Stability and Unfolding Pathways of Parallel Tetrameric G-Quadruplexes Probed by Pulling Simulations.

Guanine quadruplex (GQ) is a noncanonical nucleic acid structure formed by guanine-rich DNA and RNA sequences. Folding of GQs is a complex process, where several aspects remain elusive, despite being important for understanding structure formation and biological functions of GQs. Pulling experiments are a common tool for acquiring insights into the folding landscape of GQs. Herein, we applied a computational pulling strategy─steered molecular dynamics (SMD) simulations─in combination with standard molecular dynamics (MD) simulations to explore the unfolding landscapes of tetrameric parallel GQs. We identified anisotropic properties of elastic conformational changes, unfolding transitions, and GQ mechanical stabilities. Using a special set of structural parameters, we found that the vertical component of pulling force (perpendicular to the average G-quartet plane) plays a significant role in disrupting GQ structures and weakening their mechanical stabilities. We demonstrated that the magnitude of the vertical force component depends on the pulling anchor positions and the number of G-quartets. Typical unfolding transitions for tetrameric parallel GQs involve base unzipping, opening of the G-stem, strand slippage, and rotation to cross-like structures. The unzipping was detected as the first and dominant unfolding event, and it usually started at the 3'-end. Furthermore, results from both SMD and standard MD simulations indicate that partial spiral conformations serve as a transient ensemble during the (un)folding of GQs.

Molecular Mechanism of Interaction between DNA Aptamer and Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus 2 Variants Revealed by Steered Molecular Dynamics Simulations

The ongoing SARS-CoV-2 pandemic has underscored the urgent need for versatile and rapidly deployable antiviral strategies. While vaccines have been pivotal in controlling the spread of the virus, the emergence of new variants continues to pose significant challenges to global health. Here, our study focuses on a novel approach to antiviral therapy using DNA aptamers, short oligonucleotides with high specificity and affinity for their targets, as potential inhibitors against the spike protein of SARS-CoV-2 variants Omicron and JN.1. Our research utilizes steered molecular dynamics (SMD) simulations to elucidate the binding mechanisms of a specifically designed DNA aptamer, AM032-4, to the receptor-binding domain (RBD) of the aforementioned variants. The simulations reveal detailed molecular insights into the aptamer–RBD interaction, demonstrating the aptamer’s potential to maintain effective binding in the face of rapid viral evolution. Our work not only demonstrates the dynamic interaction between aptamer–RBD for possible antiviral therapy but also introduces a computational method to study aptamer–protein interactions.

Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis.

With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors' binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors' attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors.

Interactions and Transport of a Bioconjugated Peptide Targeting the Mitomembrane.

The Szeto-Schiller (SS) peptides are a subclass of cell-penetrating peptides that can specifically target mitochondria and mediate conditions caused by mitochondrial dysfunction. In this work, we constructed an iron-chelating SS peptide and studied its interaction with a mitochondrial-mimicking membrane using atomistic molecular dynamics (MD) simulations. We report that the peptide/membrane interaction is thermodynamically favorable, and the localization of the peptide to the membrane is driven by electrostatic interactions between the cationic residues and the anionic phospholipid headgroups. The insertion of the peptide into the membrane is driven by hydrophobic interactions between the aromatic side chains in the peptide and the lipid acyl tails. We also probed the translocation of the peptide across the membrane by applying nonequilibrium steered MD simulations and resolved the translocation pathway, free energy profile, and metastable states. We explored four distinct orientations of the peptide along the translocation pathway and found that one orientation was energetically more favorable than the other orientations. We tested a significantly slower pulling velocity on the most thermodynamically favorable system and compared metastable states during peptide translocation. We found that the peptide can optimize hydrophobic interactions with the membrane by having aromatic side chains interacting with the lipid acyl tails instead of forming π-π interactions with each other. The mechanistic insights emerging from our work will potentially facilitate improved peptide design with enhanced activity.

Application of temperature-dependent and steered molecular dynamics simulation to screen anti-dengue compounds against Marburg virus

Marburg virus infections are extremely fatal with a fatality range of 23% to 90%, therefore there is an urgent requirement to design and develop efficient therapeutic molecules. Here, a comprehensive temperature-dependent molecular dynamics (MD) simulation method was implemented to identify the potential molecule from the anti-dengue compound library that can inhibit the function of the VP24 protein of Marburg. Virtual high throughput screening identified five effective binders of VP24 after screening 484 anti-dengue compounds. These compounds were treated in MD simulation at four different temperatures: 300, 340, 380, and 420 K. Higher temperatures showed dissociation of hit compounds from the protein. Further, triplicates of 100 ns MD simulation were conducted which showed that compounds ID = 118717693, and ID = 5361 showed strong stability with the protein molecule. These compounds were further validated using Δ G binding free energies and they showed: −30.38 kcal/mol, and −67.83 kcal/mol binding free energies, respectively. Later, these two compounds were used in steered MD simulation to detect its dissociation. Compound ID = 5361 showed the maximum pulling force of 199.02 kcal/mol/nm to dissociate the protein-ligand complex while ID = 118717693 had a pulling force of 101.11 kcal/mol/nm, respectively. This ligand highest number of hydrogen bonds with varying occupancies at 89.93%, 69.80%, 57.93%, 52.33%, and 50.63%. This study showed that ID = 5361 can bind with the VP24 strongly and has the potential to inhibit its function which can be validated in the in-vitro experiment. Communicated by Ramaswamy H. Sarma

Solvent-Assisted Graphene Exfoliation from Graphite Using Umbrella Sampling Simulations.

We employed molecular dynamics (MD) simulations coupled with umbrella sampling to explore the thermodynamics governing the exfoliation of a single graphene layer from a graphitic substrate in five different solvents such as dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), cyclohexane (CHX), and water. The substrate was modeled as a stack of three identical graphene layers with the graphene sheet undergoing exfoliation positioned on top of this stack. The initial configurations for each umbrella simulation were generated through steered MD simulations carried out along two distinct coordinates: one parallel and the other perpendicular to the graphene layers. Our analyses revealed a uniform wetting behavior for both the nanosheet and the graphitic substrate in all of the tested solvents. Consistent with experimental observations, the steered simulations confirmed that exfoliation is more favorable along the parallel direction than along the perpendicular one. All non-water solvents exhibit comparable effectiveness in the exfoliation of graphene. The calculated free energies of these solvents in parallel exfoliation consistently fell within the range of 90-100 kJ/mol/nm2. In perpendicular exfoliation, however, the corresponding energies converge to lower values. This difference is attributed to the nonequilibrium nature of the perpendicular exfoliation, primarily caused by the great steering velocity of the graphene sheet immediately after detachment from the substrate. This rapid motion of the nanosheet along the perpendicular coordinate results in an elevated system energy and heating.

In-silicon studies on hydration in EcoRI-cognate DNA complex

Restriction endonucleases (REs) cleave DNA at specific site in presence of Mg2+ ion. Experiments further emphasize the role of hydration in metal ion specificity and sequence specificity of DNA cleavage. However, the relation between hydration and specificity has not been understood till date. This leads us to study via all-atom molecular dynamics (MD) simulations how the hydration around the scissile phosphate group changes in presence of Mg2+ and Ca2+ and depend on the DNA sequence. We observe the least number of hydrogen bonds around the scissile phosphate group in presence of Mg2+ ion. We further find that the hydrogen bonds decrease at the scissile phosphate on mutating one base pair in the cleavage region of the DNA in Mg2+ loaded EcoRI-DNA complex. We also perform steered MD simulations and observe that the rate of decrease of fraction of hydrogen bonds is slower in the mutated complex than the unmutated complex.

Nanoscale friction at the quartz-quartz/kaolinite interface

The nanoscale friction behavior of quartz-quartz and quartz-kaolinite interfaces is investigated through Steered Molecular Dynamics (SMD) simulations. The effects of normal load, sliding velocity, temperature, and hydration on the friction behavior are discussed, and the friction mechanism of quartz and quartz/kaolinite interface is revealed. The friction coefficients of all systems at different cases are obtained and compared with other experimental results for validation. The simulation results show that the stick-slip effect in all interfaces was found during the friction process, where the higher the sliding velocity and hydration, or the lower the normal load, the weaker the stick-slip effect. The friction load increased with the rising normal load, and the relationship between shear stress and normal load was approximately linear. The friction coefficient and cohesion of the quartz-quartz interface could rise with the increasing sliding velocity or the decreasing temperature. Moreover, the friction coefficient of quartz-kaolinite was significantly smaller than that of quartz-quartz, indicating that the presence of clay could weaken the frictional strength of quartz. The effect of the interlayer water film on friction behavior was rather complex, showing the lubricating or bonding role, which has been discussed and analyzed in the present study.

Identification of a new Kir6 potassium channel and comparison of properties of Kir6 subtypes by structural modelling and molecular dynamics

ATP-sensitive potassium ion channels (KATP) are transmembrane proteins that modulate insulin release and muscle contraction. KATP channels are composed of two types of subunit, Kir6 and SUR, which exist in two and three isoforms respectively with different tissue distribution. In this work, we identify a previously undescribed ancestral vertebrate gene encoding a Kir6-related protein that we have named Kir6.3, which may not have a SUR binding partner, unlike the other two Kir6 proteins. Whereas Kir6.3 was lost in amniotes including mammals, it is still present in several early-diverging vertebrate lineages such as frogs, coelacanth, and rayfinned fishes. Molecular dynamics (MD) simulations using homology models of Kir6.1, Kir6.2, and Kir6.3 from the coelacanth Latimeria chalumnae showed that the three proteins exhibit subtle differences in their dynamics. Steered MD simulations of Kir6-SUR pairs suggest that Kir6.3 has a lower binding affinity for the SUR proteins than either Kir6.1 or Kir6.2. As we found no additional SUR gene in the genomes of the species that have Kir6.3, it most likely forms a lone tetramer. These findings invite studies of the tissue distribution of Kir6.3 in relation to the other Kir6 as well as SUR proteins to determine the functional roles of Kir6.3.

Molecular basis of conformational changes and mechanics of integrins.

Integrin, as a mechanotransducer, establishes the mechanical reciprocity between the extracellular matrix (ECM) and cells at integrin-mediated adhesion sites. This study used steered molecular dynamics (SMD) simulations to investigate the mechanical responses of integrin αvβ3 with and without 10th type III fibronectin (FnIII10) binding for tensile, bending and torsional loading conditions. The ligand-binding integrin confirmed the integrin activation during equilibration and altered the integrin dynamics by changing the interface interaction between β-tail, hybrid and epidermal growth factor domains during initial tensile loading. The tensile deformation in integrin molecules indicated that fibronectin ligand binding modulates its mechanical responses in the folded and unfolded conformation states. The bending deformation responses of extended integrin models reveal the change in behaviour of integrin molecules in the presence of Mn2+ ion and ligand based on the application of force in the folding and unfolding directions of integrin. Furthermore, these SMD simulation results were used to predict the mechanical properties of integrin underlying the mechanism of integrin-based adhesion. The evaluation of integrin mechanics provides new insights into understanding the mechanotransmission (force transmission) between cells and ECM and contributes to developing an accurate model for integrin-mediated adhesion. This article is part of a discussion meeting issue 'Supercomputing simulations of advanced materials'.

Dissociation Rate Calculation via Constant-Force Steered Molecular Dynamics Simulation.

Steered molecular dynamics (SMD) simulations are used to study molecular dissociation events by applying a harmonic force to the molecules and pulling them at a constant velocity. Instead of constant-velocity pulling, we use a constant force: the constant-force SMD (CF-SMD) simulation. The CF-SMD simulation employs a constant force to reduce the activation barrier of molecular dissociation, thereby enhancing the dissociation event. Here, we present the capability of the CF-SMD simulation to estimate the dissociation time at equilibrium. We performed all-atom CF-SMD simulations for NaCl and protein-ligand systems, producing dissociation time at various forces. We extrapolated these values to the dissociation rate without a constant force using Bell's model or the Dudko-Hummer-Szabo model. We demonstrate that the CF-SMD simulations with the models predicted the dissociation time in equilibrium. A CF-SMD simulation is a powerful tool for estimating the dissociation rate in a direct and computationally efficient manner.

Conformational dynamics and mechanical properties of biomimetic RNA, DNA, and RNA-DNA hybrid nanotubes: an atomistic molecular dynamics study.

With the nanotechnology boom, artificially designed nucleic acid nanotubes have aroused interest due to their practical applications in nanorobotics, vaccine design, membrane channels, drug delivery, and force sensing. In this paper, computational study was performed to investigate the structural dynamics and mechanical properties of RNA nanotubes (RNTs), DNA nanotubes (DNTs), and RNA-DNA hybrid nanotubes (RDHNTs). So far, the structural and mechanical properties of RDHNTs have not been examined in experiments or theoretical calculations, and there is limited knowledge regarding these properties for RNTs. Here, the simulations were carried out using the equilibrium molecular dynamics (MD) and steered molecular dynamics (SMD) approaches. Using in-house scripting, we modeled hexagonal nanotubes composed of six double-stranded molecules connected by four-way Holliday junctions. Classical MD analyses were performed on the collected trajectory data to investigate structural properties. Analyses of the microscopic structural parameters of RDHNT indicated a structural transition from the A-form to a conformation between the A- and B-forms, which may be attributable to the increased rigidity of RNA scaffolds compared to DNA staples. Comprehensive research on the elastic mechanical properties was also conducted based on spontaneous thermal fluctuations of nanotubes and employing the equipartition theorem. The Young's modulus of RDHNT (E = 165 MPa) and RNT (E = 144 MPa) was found to be almost the same and nearly half of that found for DNT (E = 325 MPa). Furthermore, the results showed that RNT was more resistant to bending, torsional, and volumetric deformations than DNT and RDHNT. We also used non-equilibrium SMD simulations to acquire comprehensive knowledge of the mechanical response of nanotubes to tensile stress.

An Analysis of the Capturing and Passing Ability of a DNA Origami Nanocarrier with the Aid of Molecular Dynamics Simulation.

The present article aims to investigate the ability of a DNA origami nanocarrier to successfully capture a cargo using molecular dynamics (MD) simulation. In addition, the passage of the cargo through the nanocarrier was analyzed by steered molecular dynamics (SMD) simulation. The proposed DNA origami nanocarrier is a nanotube that consists of six double helices in which a positively charged nanocargo was placed. Since the stability of the nanocarrier has been considered one of the obstacles to nanocargo transportation, different cross-sectional areas of the nanocarrier were considered as measures to analyze its structural stability. The results eventually showed that the proposed nanocarrier is able to retain the cargo while maintaining its structural stability. The analysis also revealed that the presence of the cargo increases the structural stability in parts of the nanocarrier. SMD simulation demonstrated that a feasible amount of force is required to separate the cargo and pass it through the nanocarrier, which can provide useful information in the field of smart drug delivery.

Mechanical Stability of Ribonuclease A Heavily Depends on the Redox Environment.

Disulfide bonds are covalent bonds that connect nonlocal fragments of proteins, and they are unique post-translational modifications of proteins. They require the oxidizing environment to be stable, which occurs for example during oxidative stress; however, in a cell the reductive environment is maintained, lowering their stability. Despite many years of research on disulfide bonds, their role in the protein life cycle is not fully understood and seems to strictly depend on a system or process in which they are involved. In this article, coarse-grained UNited RESidue (UNRES), and all-atom Assisted Model Building with Energy Refinement (AMBER) force fields were applied to run a series of steered molecular dynamics (SMD) simulations of one of the most studied, but still not fully understood, proteins—ribonuclease A (RNase A). SMD simulations were performed to study the mechanical stability of RNase A in different oxidative–reductive environments. As disulfide bonds (and any other covalent bonds) cannot break/form in any classical all-atom force field, we applied additional restraints between sulfur atoms of reduced cysteines which were able to mimic the breaking of the disulfide bonds. On the other hand, the coarse-grained UNRES force field enables us to study the breaking/formation of the disulfide bonds and control the reducing/oxidizing environment owing to the presence of the designed distance/orientation-dependent potential. This study reveals that disulfide bonds have a strong influence on the mechanical stability of RNase A only in a highly oxidative environment. However, the local stability of the secondary structure seems to play a major factor in the overall stability of the protein. Both our thermal unfolding and mechanical stretching studies show that the most stable disulfide bond is Cys65–Cys72. The breaking of disulfide bonds Cys26–Cys84 and Cys58–Cys110 is associated with large force peaks. They are structural bridges, which are mostly responsible for stabilizing the RNase A conformation, while the presence of the remaining two bonds (Cys65–Cys72 and Cys40–Cys95) is most likely connected with the enzymatic activity rather than the structural stability of RNase A in the cytoplasm. Our results prove that disulfide bonds are indeed stabilizing fragments of the proteins, but their role is strongly redox environment-dependent.

Optimal control with a strong harmonic trap.

Quadratic trapping potentials are widely used to experimentally probe biopolymers and molecular machines and drive transitions in steered molecular-dynamics simulations. Approximating energy landscapes as locally quadratic, we design multidimensional trapping protocols that minimize dissipation. The designed protocols are easily solvable and applicable to a wide range of systems. The approximation does not rely on either fast or slow limits and is valid for any duration provided the trapping potential is sufficiently strong. We demonstrate the utility of the designed protocols with a simple model of a periodically driven rotary motor. Our results elucidate principles of effective single-molecule manipulation and efficient nonequilibrium free-energy estimation.

Protein aggregation rate depends on mechanical stability of fibrillar structure.

The formation of the fibrillar structure of amyloid proteins/peptides is believed to be associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Since the rate of aggregation can influence neurotoxicity, finding the key factors that control this rate is of paramount importance. It was recently found that the rate of protein aggregation is related to the mechanical stability of the fibrillar structure such that the higher the mechanical stability, the faster the fibril is formed. However, this conclusion was supported by a limited dataset. In this work, we expand the previous study to a larger dataset, including the wild type of Aβ42 peptide and its 20 mutants, the aggregation rate of which was measured experimentally. By using all-atom steered molecular dynamics (SMD) simulations, we can assess the mechanical stability of the fibril structure, which is characterized by the rupture force, pulling work, and unbinding free energy barrier. Our result confirms that mechanical stability is indeed related to the aggregation rate. Since the estimation of the aggregation rate using all-atom simulations is almost forbidden by the current computational capabilities, our result is useful for predicting it based on information obtained from fast SMD simulations for fibrils.

Efficient two-dimensional control of barrier crossing

Driven barrier crossings are pervasive in optical-trapping experiments and steered molecular-dynamics simulations. Despite the high fidelity of control, the freedom in the choice of driving protocol is rarely exploited to improve efficiency. We design protocols that reduce dissipation for rapidly driven barrier crossing under two-dimensional control of a harmonic trapping potential, controlling both trap center and stiffness. For fast driving, the minimum-dissipation protocol jumps halfway between the control-parameter endpoints. For slow driving, the minimum-dissipation protocol generically slows down and tightens the trap as it crosses the barrier, resulting in both significant energy savings and increased flux compared to naive and one-dimensional protocols (that only change trap center). Combining fast and slow results, we design protocols that improve performance at all speeds.

Searching for AChE inhibitors from natural compounds by using machine learning and atomistic simulations

Acetylcholinesterase (AChE) is one of the most important drug targets for Alzheimer's disease treatment. In this work, a combined approach involving machine-learning (ML) model and atomistic simulations was established to predict the ligand-binding affinity to AChE of the natural compounds from VIETHERB database. The trained ML model was first utilized to rapidly and accurately screen the natural compound database for potential AChE inhibitors. Atomistic simulations including molecular docking and steered-molecular dynamics simulations were then used to confirm the ML outcome. Good agreement between ML and atomistic simulations was observed. Twenty compounds were suggested to be able to inhibit AChE. Especially, four of them including geranylgeranyl diphosphate, 2-phosphoglyceric acid, and 2-carboxy-d-arabinitol 1-phosphate, and farnesyl diphosphate are highly potent inhibitors with sub-nanomolar affinities.

An integrated approach reveals how lipo-chitooligosaccharides interact with the lysin motif receptor-like kinase MtLYR3.

N‐acetylglucosamine containing compounds acting as pathogenic or symbiotic signals are perceived by plant‐specific Lysin Motif Receptor‐Like Kinases (LysM‐RLKs). The molecular mechanisms of this perception are not fully understood, notably those of lipo‐chitooligosaccharides (LCOs) produced during root endosymbioses with nitrogen‐fixing bacteria or arbuscular mycorrhizal fungi. In Medicago truncatula, we previously identified the LysM‐RLK LYR3 (MtLYR3) as a specific LCO‐binding protein. We also showed that the absence of LCO binding to LYR3 of the non‐mycorrhizal Lupinus angustifolius, (LanLYR3), was related to LysM3, which differs from that of MtLYR3 by several amino acids and, particularly, by a critical tyrosine residue absent in LanLYR3. Here, we aimed to define the LCO binding site of MtLYR3 by using molecular modelling and simulation approaches, combined with site‐directed mutagenesis and LCO binding experiments. 3D models of MtLYR3 and LanLYR3 ectodomains were built, and homology modelling and molecular dynamics (MD) simulations were performed. Molecular docking and MD simulation on the LysM3 identified potential key residues for LCO binding. We highlighted by steered MD simulations that in addition to the critical tyrosine, two other residues were important for LCO binding in MtLYR3. Substitution of these residues in LanLYR3‐LysM3 by those of MtLYR3‐LysM3 allowed the recovery of high‐affinity LCO binding in experimental radioligand‐binding assays. An analysis of selective constraints revealed that the critical tyrosine has experienced positive selection pressure and is absent in some LYR3 proteins. These findings now pave the way to uncover the functional significance of this specific evolutionary pattern.

Molecular dynamics simulations of the secondary-binding site in disaccharide-modified glycopeptide antibiotics

Oritavancin is a semisynthetic glycopeptide antibiotic used to treat severe infections by multidrug-resistant Gram-positive pathogens. Oritavancin is known to be a thousand times more potent than vancomycin against Gram-positive bacteria due to the additional interactions with bacterial peptidoglycan (PG) facilitated by a secondary-binding site. The presence of this secondary-binding site is evident in desleucyl-oritavancin, an Edman degradation product of oritavancin, still retaining its potency against Gram-positive bacteria, whereas desleucyl-vancomycin is devoid of any antimicrobial activities. Herein, using explicit solvent molecular dynamics (MD) simulations, steered MD simulations, and umbrella sampling, we show evidence of a secondary-binding site mediated by the disaccharide-modified hydrophobic sidechain of oritavancin interactions with the pentaglycyl-bridge segment of the PG. The interactions were characterized through comparison to the interaction of PG with chloroeremomycin, vancomycin, and the desleucyl analogs of the glycopeptides. Our results show that the enhanced binding of oritavancin to PG over the binding of the other complexes studied is due to an increase in the hydrophobic effect, electrostatic and van der Waals interactions, and not the average number of hydrogen bonds. Our ranking of the binding interactions of the biomolecular complexes directly correlates with the order based on their experimental minimum inhibitory concentrations. The results of our simulations provide insight into the modification of glycopeptides to increase their antimicrobial activities or the design of novel antibiotics against pathogenic Gram-positive bacteria.