Effects of lipid composition on membrane distribution and permeability of natural quinones

Natural quinones are amphiphilic molecules that function as mobile charge carriers in biological energy transduction. Their distribution and permeation across membranes are important for binding to enzymatic complexes and for proton translocation. Here, we employ molecular dynamics simulations and free energy calculations with a carefully calibrated classical force-field to probe quinone distribution and permeation in a multi-component bilayer trying to mimic the composition of membranes involved in bioenergetic processes. Ubiquinone, ubiquinol, plastoquinone and menaquinone molecules with short and long isoprenoid tails are simulated. We find that penetration of water molecules bound to the polar quinone head increases considerably in the less ordered and porous bilayer formed by di-linoleoyl (18:2) phospholipids, resulting in a lower free energy barrier for quinone permeation and faster transversal diffusion. In equilibrium, quinone and quinol heads localize preferentially near lipid glycerol groups, but do not perform specific contacts with lipid polar heads. Quinone distribution is not altered significantly by the quinone head, tail and lipid composition in comparison to a single-component bilayer. This study highlights the role of lipid acyl chain unsaturation for permeation and transversal diffusion of polar molecules across biological membranes.

Lipid acyl chain unsaturation modulates the barrier for ubiquinone flip-flop over the membrane.     

Molecular mechanism of the skin permeation enhancing effect of ethanol: a molecular dynamics study

Ethanol is widely used in various pharmaceutical and cosmetic formulations in order to enhance skin penetration of active ingredients. While it is well known that ethanol partitions into the skin and enhances the permeation of both polar and nonpolar molecules, the exact mechanisms by which it enhances skin permeability are not fully understood. Several mechanisms have been proposed including lipid extraction from the stratum corneum (SC), fluidisation of SC lipid bilayer, alteration of SC protein conformation and enhancement of the drug solubility in the SC lipids. In this study, we performed molecular dynamics (MD) simulations of SC lipid bilayers comprised of an equimolar mixture of ceramides, cholesterol and free fatty acid in the presence of aqueous mixtures of ethanol. Various unrestrained MD simulations were performed in the presence of aqueous ethanol solution at molar ratios (x) ranging from x = 0 to x = 1. It was found that ethanol enhances bilayer permeability by dual actions (a) extraction of the skin lipids and (b) enhancing the mobility of lipid chains. Ethanol''s permeation enhancing effect arises from its superior ability to form hydrogen bonds with headgroup atoms of skin lipids. Further, the free energy of extraction of ceramides (CER) and fatty acids (FFA) from the lipid bilayer was studied using umbrella sampling simulations. The free energy of extraction of CER was found to be much higher compared to FFA for all ethanol concentrations which shows that CER are difficult to extract as compared to FFA. Finally, the permeation of benzoic acid drug molecules through the skin lipid bilayer is shown in presence of ethanol molecules. It was found that ethanol selectively targets the FFA of the skin lipid bilayer and extracts it out of the lipid bilayer within few microseconds. Further, ethanol penetrates inside the lipid layer and creates the channels from which drug molecules can easily cross the lipid layer. Our observations (both in unrestrained and umbrella sampling simulations) are consistent with the experimental findings reported in the literature. The simulation methodology could be used for design and testing of permeation enhancers (acting on skin SC lipid lamella) for topical and transdermal drug delivery applications.

Concentration dependent action of mechanism of ethanol on skin SC lipid barrier.     

Interactions of neutral gold nanoparticles with DPPC and POPC lipid bilayers: simulation and experiment

Molecular dynamics simulations of neutral gold nanoparticles (AuNPs) interacting with dipalmitoylphosphatidylcholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes were studied using a model system. Spontaneous membrane insertion of AuNPs did not occur on the time scale of atomistic simulations. To overcome the limitations of time scale, we used a harmonic restraining potential to force the AuNPs into the membranes. Free energy calculations indicate that a NP has to cross a free energy barrier of about 134 kJ mol⁻¹ prior to forming a stable contact with the membrane. This energy barrier between lipids and NPs comes from the repulsion between headgroups of lipids and AuNPs. The experimental investigations indicate that, contrary to hydrophobic AuNPs, neutral AuNPs cannot form ion channels across lipid membranes. The adsorption of NPs induces the formation of a highly ordered region in phospholipid bilayers. Our simulation results propose that the cell penetration of small uncoated AuNPs does not involve energy-independent membrane translocation but rather involves the energy-dependent formation of nanoscale membrane holes or energy-dependent endocytosis.

Molecular dynamics simulations of neutral gold nanoparticles (AuNPs) interacting with dipalmitoylphosphatidylcholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes were studied using a model system.     

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

Cyclic peptides have the potential to vastly extend the scope of druggable proteins and lead to new therapeutics for currently untreatable diseases. However, cyclic peptides often suffer from poor bioavailability. To uncover design principles for permeable cyclic peptides, a promising strategy is to analyze the conformational dynamics of the peptides using molecular dynamics (MD) and Markov state models (MSMs). Previous MD studies have focused on the conformational dynamics in pure aqueous or apolar environments to rationalize membrane permeability. However, during the key steps of the permeation through the membrane, cyclic peptides are exposed to interfaces between polar and apolar regions. Recent studies revealed that these interfaces constitute the free energy minima of the permeation process. Thus, a deeper understanding of the behavior of cyclic peptides at polar/apolar interfaces is desired. Here, we investigate the conformational and kinetic behavior of cyclic decapeptides at a water/chloroform interface using unbiased MD simulations and MSMs. The distinct environments at the interface alter the conformational equilibrium as well as the interconversion kinetics of cyclic peptide conformations. For peptides with low population of the permeable conformation in aqueous solution, the polar/apolar interface facilitates the interconversion to the closed conformation, which is required for membrane permeation. Comparison to unbiased MD simulations with a POPC bilayer reveals that not only the conformations but also the orientations are relevant in a membrane system. These findings allow us to propose a permeability model that includes both ‘prefolding’ and ‘non-prefolding’ cyclic peptides – an extension that can lead to new design considerations for permeable cyclic peptides.

This study uses molecular dynamics and Markov state models to analyse how interfaces interact with cyclic decapeptides and modulate their dynamic and equilibrium properties.     

Enhanced water permeability across a physiological droplet interface bilayer doped with fullerenes

We measure the water permeability across a physiological lipid bilayer produced by the droplet interface bilayer (DiB) technique. This lipid bilayer can be considered as physiologically relevant because it presents a lipidic composition close to human cell membranes. The measured water permeability coefficients across this lipid bilayer are reported as a function of the cholesterol concentration. It is found that the water permeability coefficients decreased with increasing cholesterol concentration, in agreement with the existing literature. And, consistently, the extracted corresponding activation energies increase with increasing cholesterol concentration in the lipid bilayer. Hence having demonstrated the robustness of the experimental system, we extend this study by exploring the influence of fullerenes on the water permeability of a physiological lipid bilayer. Interestingly, we observe a significant increase of the measured water permeability coefficients across this lipid bilayer for large fullerenes concentration. This enhanced permeability might be related to the conductive properties of fullerenes.

We measure the water permeability across a physiological lipid bilayer produced by the droplet interface bilayer technique.     

Role of polyunsaturated phospholipids in liquid-ordered and liquid-disordered phases

Polyunsaturated phospholipids interact complexly with other membrane components. We have examined pair interactions among ternary lipid bilayers composed of saturated DPPC, polyunsaturated PLePC, and cholesterol in the liquid-ordered and the liquid-disordered phases by all-atom molecular dynamics simulations. The results show that PLePC exhibits strong repulsion with DPPC and cholesterol in the liquid-disordered phase. When the bilayer changes to the liquid-ordered phase, the repulsion of PLePC with DPPC and cholesterol reduces significantly. The phase state of the bilayer which affects the order of acyl tails as well as their density distributions along the bilayer normal is a key factor regulating the role of PLePC in lipid mixtures. Polyunsaturated phospholipids play a strong repulsive role in the liquid-disordered phase but a weak role in the liquid-ordered phase.

Polyunsaturated phospholipids play a strong repulsive role in the liquid-disordered phase but a weak role in the liquid-ordered phase.     

Lipid membrane interactions of self-assembling antimicrobial nanofibers: effect of PEGylation

Supramolecular assembly and PEGylation (attachment of a polyethylene glycol polymer chain) of peptides can be an effective strategy to develop antimicrobial peptides with increased stability, antimicrobial efficacy and hemocompatibility. However, how the self-assembly properties and PEGylation affect their lipid membrane interaction is still an unanswered question. In this work, we use state-of-the-art small angle X-ray and neutron scattering (SAXS/SANS) together with neutron reflectometry (NR) to study the membrane interaction of a series of multidomain peptides, with and without PEGylation, known to self-assemble into nanofibers. Our approach allows us to study both how the structure of the peptide and the membrane are affected by the peptide–lipid interactions. When comparing self-assembled peptides with monomeric peptides that are not able to undergo assembly due to shorter chain length, we found that the nanofibers interact more strongly with the membrane. They were found to insert into the core of the membrane as well as to absorb as intact fibres on the surface. Based on the presented results, PEGylation of the multidomain peptides leads to a slight net decrease in the membrane interaction, while the distribution of the peptide at the interface is similar to the non-PEGylated peptides. Based on the structural information, we showed that nanofibers were partially disrupted upon interaction with phospholipid membranes. This is in contrast with the considerable physical stability of the peptide in solution, which is desirable for an extended in vivo circulation time.

Wrane interaction of a series of self-assembling antimicrobial peptides with and without PEGylation using small angle X-ray and neutron scattering and neutron reflectometry.     

Fullerene translocation through peroxidized lipid membranes

Recent cytotoxicity research suggests that fullerenes can enter the cell and cross the blood–brain barrier. However, the underlying toxicity mechanism behind the penetration of fullerenes through biological membranes is still not well understood. Here we perform coarse-grained molecular dynamics simulations to investigate the interactions of fullerenes and their polar derivatives (Janus) with model regular and peroxidized bilayers. We show that the translocation of fullerenes and their residence time in bulk water vary depending on the bilayer''s peroxidation degree and fullerene polarity. The distribution of fullerenes inside the bilayer is mainly determined by the peroxidation degree and the saturation level of lipid acyl chains. The transport of pristine fullerenes through bilayers occurs at nano timescale while the complete diffusion may not be achieved for Janus fullerenes in micro timescale. As for the toxic response of fullerenes in terms of membrane damage, no mechanical disruption of model bilayers is observed throughout the studied simulation times.

The translocation of fullerenes and their polar conjugates (Janus) is investigated across model membranes and their different peroxidized forms.     

The F19W mutation reduces the binding affinity of the transmembrane Aβ11–40 trimer to the membrane bilayer

Alzheimer''s disease is linked to the aggregation of the amyloid-β protein (Aβ) of 40 or 42 amino acids. Lipid membranes are known to modulate the rate and mechanisms of the Aβ aggregation. Point mutations in Aβ can alter these rates and mechanisms. In particular, experiments show that F19 mutations influence the aggregation rate, but maintain the fibril structures. Here, we used molecular dynamics simulations to examine the effect of the F19W mutation in the 3Aβ_11–40 trimer immersed in DPPC lipid bilayers submerged in aqueous solution. Substituting Phe by its closest (non-polar) aromatic amino acid Trp has a dramatic reduction in binding affinity to the phospholipid membrane (measured with respect to the solvated protein) compared to the wild type: the binding free energy of the protein–DPPC lipid bilayer increases by 40–50 kcal mol⁻¹ over the wild-type. This is accompanied by conformational changes and loss of salt bridges, as well as a more complex free energy surface, all indicative of a more flexible and less stable mutated trimer. These results suggest that the impact of mutations can be assessed, at least partially, by evaluating the interaction of the mutated peptides with the lipid membranes.

Dominant conformations of F19W 3Aβ_11–40 immersed in transmembrane DPPC lipid bilayer submerged in aqueous solution.     

Mechanisms underlying interactions between PAMAM dendron-grafted surfaces with DPPC membranes

Biofouling is a pervasive problem which demands the creation of smart, antifouling surfaces. Towards this end, we examine the interactions between a dipalmitoylphosphatidylcholine (DPPC) lipid bilayer and a polyamidoamine (PAMAM) dendron-grafted surface. In addition, we investigate the impact of dendron generation on the system behavior. To resolve the multiscale dynamical processes occurring over a large spatial scale, we employ Molecular Dynamics simulations with a coarse-grained implicit solvent force field. Our results demonstrate the transient and equilibrium system dynamics to be determined by the PAMAM dendron generation along with the underlying mechanisms. Higher generation dendrons are observed to favor penetration of the DPPC molecules into the dendron branches, thereby enabling sustained interactions between the membrane and the dendron-grafted surface. Under equilibrium, the membrane adopts a bowl-shaped morphology whose dimensions are determined by the dendron generation and density of interactions. The results from our study can be used to guide the design of novel surfaces with selective antifouling properties which can prevent the adsorption of microorganisms onto lipid membranes.

The interactions between a DPPC lipid membrane and a PAMAM dendron-grafted surface.     

A mechanoresponsive nano-sized carrier achieves intracellular release of drug on external ultrasound stimulus

Control over intracellular release of therapeutic compounds incorporated into nano-carriers will open new possibilities for targeted treatments of various diseases including cancer, and viral and bacterial infections. Here we report our study on mechanoresponsive nano-sized liposomes which, following internalization by cells, achieve intracellular delivery of encapsulated cargo on application of external ultrasound stimulus. This is demonstrated in a bespoke cell reporter system designed to assess free drug in cytoplasm. Biophysical analyses show that drug release is attributable to the action of a mechanoresponsive spiropyran-based compound embedded in the liposomal lipid membrane. Exposure to external ultrasound stimulus results in opening of the molecular structure of the embedded spiropyran, a consequent increase in liposomal lipid membrane fluidity, and size-dependent release of encapsulated model drugs, all pointing to lipid bilayer perturbation. The study hence illustrates feasibility of the proposed concept where intracellular drug release from mechanoresponsive liposomes can be triggered on demand by external ultrasound stimulus.

The study illustrates feasibility of the proposed concept where intracellular drug release from mechanoresponsive liposomes can be triggered on demand by external ultrasound stimulus.     

Structure and dynamics of liposomes designed for drug delivery: coarse-grained molecular dynamics simulations to reveal the role of lipopolymer incorporation

In this work, coarse-grained molecular dynamics simulations are carried out in NPTH and NVTE statistical ensembles in order to study the structure and dynamics properties of liposomes coated with polyethylene glycol (PEG). The considered liposomes are made by membrane bilayer DPPC with DPPC-PEG incorporated lipopolymers, in an aqueous environment. We have described the two essential PEG conformation regimes, mushroom and brush, and their properties which depend on the grafting density. The effects of grafting density on the structure and dynamics of the membrane were also studied. Our simulations were then discussed by comparing with the available experimental results and by referring to the suitable theoretical models. The results from the NPTH simulations agree with the experimental data of X-ray diffraction and with scale and mean-field theories in terms of thickness of the PEG layer and thickness of the DPPC bilayer membrane. The results from NVTE simulations are found in good agreement with the experimental results from studying the diffusion of the DPPC bilayer membrane and the PEG. The analysis of the mean square displacement revealed that the dynamics of the membranes in the plane show a subdiffusion due to the cage effect and that the grafted PEG dynamics is better described by the Rouse diffusion-mode. Thus, from a macroscopic viewpoint, the incorporation of DPPC-PEG plays an important role in the protection and lubrication of the liposome.

In this work, coarse-grained molecular dynamics simulations are carried out in NPTH and NVTE statistical ensembles in order to study the structure and dynamics properties of liposomes coated with polyethylene glycol (PEG).     

Membrane partition of bis-(3-hydroxy-4-pyridinonato) zinc(ii) complexes revealed by molecular dynamics simulations

The class of 3-hydroxy-4-pyridinone ligands is widely known and valuable for biomedical and pharmaceutical purposes. Their chelating properties towards biologically-relevant transition metal ions highlight their potential biomedical utility. A set of 3-hydroxy-4-pyridinone Zn(ii) complexes at different concentrations was studied for their ability to interact with lipid phases. We employed umbrella sampling simulations to attain the potential-of-mean force for a set of ligands and one Zn(ii) complex, as these permeated a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) hydrated bilayer system. In addition, we used conventional molecular dynamics simulations to study the behavior of various Zn(ii) complexes in hydrated bilayer systems. This work discusses: (i) the partition of 3-hydroxy-4-pyridinone ligands to bilayer phases; (ii) self-aggregation in crowded environments of Zn(ii) complexes; and (iii) possible mechanisms for the membrane translocation of Zn(ii) complexes. We observed distinct interactions for the studied complexes, and distinct membrane partition coefficients (K_mem) depending on the considered ligand. The more hydrophobic ligand, 1-hexyl-3-hydroxy-2-methyl-4(1H)-pyridinone, partitioned more favorably to lipid phases (at least two orders of magnitude higher K_mem when compared to the other ligands), and the corresponding Zn(ii) complex was also prone to self-aggregation when an increased concentration of the complex was employed. We also observed that the inclusion of a coordinated water molecule in the parameterization of the Zn(ii) coordination sphere, as proposed in the available crystallographic structure of the complex, decreased the partition coefficient and membrane permeability for the tested complex.

The membrane partition of hydroxypyridinones and of zinc complexes explored by molecular dynamics.     

Thermo-driven self-assembly of a PEG-containing amphiphile in a bilayer membrane

Self-assembly of lipid molecules in a plasma membrane, namely lipid raft formation, is involved in various dynamic functions of cells. Inspired by the raft formation observed in the cells, here we studied thermally induced self-assembly of a synthetic amphiphile, bola-AkDPA, in a bilayer membrane. The synthetic amphiphile consists of a hydrophobic unit including fluorescent aromatic and aliphatic components and hydrophilic tetraethylene glycol chains attached at both ends of the hydrophobic unit. In a polar solvent, bola-AkDPA formed aggregates to show excimer emission. In a lipid bilayer membrane, bola-AkDPA showed intensified excimer emission upon increase of its concentration or elevation of the temperature; bola-type amphiphiles containing oligoethylene glycol chains likely tend to form self-assemblies in a bilayer membrane triggered by thermal stimuli.

A synthetic multi-block amphiphile containing oligoethylene glycol chains formed a self-assembly in a bilayer membrane triggered by thermal stimuli.     

Interactions of a paracyclophane-based conjugated oligoelectrolyte with biological membranes

A three-dimensional conjugated oligoelectrolyte (COE) bearing a [2.2]paracyclophane unit (COE2-3-pCp) was synthesized. Its biological activity was determined both in vivo and in silico within the context of membrane perturbation and biocompatibility. Molecular dynamics simulations indicate that, compared to its linear analog (COE2-3C), COE2-3-pCp introduces more lipid disorder with higher extent of membrane thinning. COE2-3-pCp also exhibits a higher MIC towards E. coli K12 and yeast, while maintaining similar levels of membrane permeabilization. These findings suggest a new design of COEs as biocompatible cell permeabilizers.

We report a non-planar conjugated oligoelectrolyte as a membrane permeabilizing material and its membrane interactions compared to the linear analog.     

Effect of C60 on the phase transition behavior of a lipid bilayer under high pressure

Interactions between fullerenes and cells and effects on the main transition of lipid bilayers have attracted much attention in biophysics in recent years. By employing coarse-grained molecular dynamics simulations, we obtained the temperature–pressure phase diagrams of a dipalmitoylphosphatidylcholine bilayer, which exhibits a gel phase and a fluid phase, with variation of the C₆₀versus lipid ratios. The simulation results show that the critical area per lipid at the fluid–gel main phase transition boundary increases with the increasing ratios of C₆₀. A critical area per lipid of 0.594 ± 0.002 nm² is obtained when the ratio of C₆₀ reaches 6.4% while that of the pure bilayer case is 0.572 ± 0.002 nm². The main transition temperature, T_m, remains almost unchanged with the addition of C₆₀ below a ratio of 4.7%, while a 2 K decrease of T_m is observed at a ratio of 6.4% under various pressures. Consequently, the presence of C₆₀ in the bilayer, with the ratio of C₆₀ less than 4.7%, will not influence the main transition behavior of the bilayer even under pressure as high as 1500 bar. The radial distribution function analyses suggest that the presence of C₆₀ produces no impact on the radial distribution of the lipids in the bilayers. The lateral density profiles show that the incorporation of C₆₀ with relatively high ratios stabilizes the thickness of the bilayer.

By employing coarse-grained molecular dynamics simulations, we obtained the temperature–pressure phase diagrams of a dipalmitoylphosphatidylcholine bilayer, which exhibits a gel phase and a fluid phase, with variation of the C₆₀versus lipid ratios.      

Effects of cholesterol on bilayers with various degrees of unsaturation of their phospholipid tails under mechanical stress

Cholesterol is one of the essential components of the cell membrane. It has a significant influence on various mechanical properties of biomembranes, such as fluidity and elasticity, which have attracted much attention. It is also well known that the concentration of cholesterol affects the mechanical strength of cell membranes. In this paper, we aim to explore the influence of the degree of unsaturation of phospholipid tails on the concentration-effect of cholesterol. Three different phospholipids (DPPC, DIPC and DAPC) were selected as the respective main components of the bilayers and several concentrations of cholesterol were also added to the systems. Our coarse-grained molecular dynamics simulations show that as the cholesterol concentration increases, the saturated phospholipid bilayer is first strengthened, by increasing the rupture tension from 68.9 to 110 mN m⁻¹, and then weakened. The non-monotonic concentration-effect gradually decreases as the degree of unsaturation of the phospholipid tails increases, and in particular, the mechanical strength of the DAPC bilayer hardly changes. The results suggest that cholesterol does not influence a bilayer composed of highly unsaturated phospholipids. Furthermore, lateral density distributions reveal that the distribution of cholesterol in the bilayer is related to the carbon tail unsaturation of the phospholipids.

The concentration-effect of cholesterol on the mechanical strength of biomembranes weakens as the degree of unsaturation of the phospholipid tails increases.     

Evaluation of all-atom force fields in viral capsid simulations and properties

As the past century has been characterized by waves of viral pandemics, there is an ever-growing role for molecular simulation-based research. In this study, we utilize all-atom molecular dynamics to simulate an enterovirus-D68 capsid and examine the dependency of viral capsid dynamics and properties on AMBER and CHARMM force fields. Out of the six force fields studied, we note that CHARMM36m and CHARMM36 generate secondary structures that are most consistent with protein structural data and sample the largest conformational space. The ion distribution and radius of gyration of the capsid are similar across all force fields investigated.

We investigate six AMBER and CHARMM force fields for molecular dynamics simulations of viral capsids. Out of the force fields studied, we recommend CHARMM36m and CHARMM36 for future use.     

Collective absorption of 2,4,6-trinitrotoluene into lipid membranes and its effects on bilayer properties. A computational study

The widely used explosive, 2,4,6-trinitrotoluene (TNT), is a highly toxic chemical, which can cause hepatitis, cataracts, jaundice and so on, in humans. The interaction between TNT and biological membranes is crucial for understanding its toxic effects. Here, we mainly focused on molecular-level mechanisms for the collective adsorption of TNT into lipid membranes and the corresponding effects on bilayer properties by all-atom molecular dynamics simulations. We revealed that TNT can readily form an aggregate in the aqueous phase and quickly approach the surface of the membrane. At low concentrations of TNT (7 mol%), the aggregate is unstable and breaks up after several nanoseconds, and then the dispersed TNT molecules enter the membrane alone. At high concentrations (14 mol%), the aggregate is adsorbed as a whole and remains stable inside the membrane. After some of the TNT is absorbed by the membrane, the remaining TNT across the membrane would have greater permeability, i.e., the calculated permeability coefficient (P) is increased from 1.7 × 10⁻² to 18.3 cm s⁻¹. Correspondingly, a higher bioconcentration factor (BCF) was also observed. The increased level is more pronounced in the presence of TNT aggregates (i.e., high concentrations). This phenomenon is closely related to the strong interaction between TNT molecules. The results suggested that TNT molecules that have entered into the membrane can facilitate the membrane uptake, permeation and bioaccumulation of subsequent TNT molecules, exhibiting a synergistic effect. This work has a certain significance for understanding the toxicity of TNT.

The widely used explosive, 2,4,6-trinitrotoluene (TNT), is a highly toxic chemical, which can cause hepatitis, cataracts, jaundice and so on, in humans.     

Anomalous dynamics of water at the octopeptide lanreotide surface

This work reports the study of water dynamics close to the cyclic octapeptide lanreotide from atomistic simulations of hydrated lanreotide, a cyclic octapeptide. Calculation of the hydrogen bonds between water molecules allows mapping of the hydrophilic regions of lanreotide. Whereas a super-diffusivity of the interfacial water molecules is established, a slowdown in rotational dynamics is observed, involving a decoupling between both processes. Acceleration in translation dynamics is connected to the hopping process between hydrophilic zones. Microscopically, this is correlated with the weakness of the interfacial hydrogen bonding network due to a hydrophobic interface at the origin of the interfacial sliding of water molecules. Heterogeneous rotational dynamics of water molecules close the lanreotide surface is evidenced and connected to heterogeneous hydration.

Molecular dynamics simulations of a hydrated mutated lanreotide, a cyclic octapeptide, were carried out to characterize its hydration state. We studied the water dynamics close to the peptide using atomistic simulations.