Structure and dynamics of double-stranded DNA rotaxanes.

A DNA rotaxane, with its unique mechanically interlocked architecture consisting of a circular DNA molecule threaded onto a linear DNA axle, holds promise as a fundamental component for nanoscale functional devices. Nevertheless, its structural and dynamic behaviors, essential for advancing molecular machinery, remain largely unexplored. Using extensive all-atom molecular dynamics simulations, we investigated the behaviors of double-stranded DNA (dsDNA) rotaxanes, concentrating on the effects of shape distortion induced by torsional stress in small circular dsDNA containing 70-90 base pairs. We analyzed structural characteristics, including shape, intermolecular distances, and tilt angles, while also exploring dynamic properties such as translational diffusion and toroidal rotation. Our results indicate that shape distortion brings the circular and linear dsDNA components into closer proximity and causes a slight increase in translational diffusion yet a minor decrease in toroidal rotation. Nevertheless, there is no apparent evidence of coupling between translation and rotation. Overall, the insights from this study indicate that such shape distortion does not significantly alter their structure and dynamics. This finding provides flexibility for the design of DNA rotaxanes in nanoscale applications.

Molecular Dynamics Simulation Study of the Protonation State Dependence of Glutamic Acid Transport through a Cyclic Peptide Nanotube.

The effect of the protonation state of glutamic acid on its translocation through cyclic peptide nanotubes (CPNs) was assessed by using molecular dynamics (MD) simulations. Anionic (GLU-), neutral zwitterionic (GLU0), and cationic (GLU+) forms of glutamic acid were selected as three different protonation states for an analysis of energetics and diffusivity for acid transport across a cyclic decapeptide nanotube. Based on the solubility-diffusion model, permeability coefficients for the three protonation states of the acid were calculated and compared with experimental results for CPN-mediated glutamate transport through CPNs. Potential of mean force (PMF) calculations reveal that, due to the cation-selective nature of the lumen of CPNs, GLU-, so-called glutamate, shows significantly high free energy barriers, while GLU+ displays deep energy wells and GLU0 has mild free energy barriers and wells inside the CPN. The considerable energy barriers for GLU- inside CPNs are mainly attributed to unfavorable interactions with DMPC bilayers and CPNs and are reduced by favorable interactions with channel water molecules through attractive electrostatic interactions and hydrogen bonding. Unlike the distinct PMF curves, position-dependent diffusion coefficient profiles exhibit comparable frictional behaviors regardless of the charge status of three protonation states due to similar confined environments imposed by the lumen of the CPN. The calculated permeability coefficients for the three protonation states clearly demonstrate that glutamic acid has a strong protonation state dependence for its transport through CPNs, as determined by the energetics rather than the diffusivity of the protonation state. In addition, the permeability coefficients also imply that GLU- is unlikely to pass through a CPN due to the high energy barriers inside the CPN, which is in disagreement with experimental measurements, where a considerable amount of glutamate permeating through the CPN was detected. To resolve the discrepancy between this work and the experimental observations, several possibilities are proposed, including a large concentration gradient of glutamate between the inside and outside of lipid vesicles and bilayers in the experiments, the glutamate activity difference between our MD simulations and experiments, an overestimation of energy barriers due to the artifacts imposed in MD simulations, and/or finally a transformation of the protonation state from GLU- to GLU0 to reduce the energy barriers. Overall, our study demonstrates that the protonation state of glutamic acid has a strong effect on the transport of the acid and suggests a possible protonation state change for glutamate permeating through CPNs.

Molecular Dynamics Simulations of Micelle Properties and Behaviors of Sodium Lauryl Ether Sulfate Penetrating Ceramide and Phospholipid Bilayers.

Molecular dynamics (MD) simulations with the umbrella sampling (US) method were used to investigate the properties of micelles formed by sodium lauryl ether sulfate with two ether groups (SLE2S) and behaviors of corresponding surfactants transferring from micelles to ceramide and DMPC bilayer surfaces. Average micelle radii based on the Einstein-Smoluchowski and Stokes-Einstein relations showed excellent agreement with those measured by dynamic light scattering, while those obtained by evaluating the gyration radius or calculating the distance between the micelle sulfur atoms and center of mass overestimate the radii. As an SLE2S micelle was pulled down to the ceramide bilayer surface in a 400 ns constant-force steered MD (cf-SMD) simulation, the micelle was partially deformed on the bilayer surface, and several SLE2S surfactants easily were partitioned from the micelle into the ceramide bilayer. In contrast, a micelle was not deformed on the DMPC bilayer surface, and SLE2S surfactants were not transferred from the micelle to the DMPC bilayer. Potential of mean force (PMF) calculations revealed that the Gibbs free energy required for an SLE2S surfactant monomer to transfer from a micelle to bulk water can be compensated by decreased Gibbs free energy when an SLE2S monomer transfers into the ceramide bilayer from bulk water. In addition, micelle deformation on the ceramide bilayer surface can reduce the Gibbs free energy barrier required for a surfactant to escape the micelle and help the surfactant partition from the micelle into the ceramide bilayer. An SLE2S surfactant partitioning into the ceramide bilayer is attributed to hydrogen bonding and favorable interactions between the hydrophilic surfactant head and ceramide molecules, which are more dominant than the dehydration penalty during bilayer insertion. Such interactions between surfactant and lipid molecule heads are considerably reduced in DMPC bilayers owing to dielectric screening by water molecules deep inside the head/tail boundary between the DMPC bilayer. This computational work demonstrates the distinct behavior of SLE2S surfactant micelles on ceramide and DMPC bilayer surfaces in terms of variation in Gibbs free energy, which offers insight into designing surfactants used in transdermal drug delivery systems and cosmetics.

Conformational Effects in the Transport of Glucose through a Cyclic Peptide Nanotube: A Molecular Dynamics Simulation Study.

The transport behavior of glucose through a cyclic peptide nanotube (CPN), composed of 8 × cyclo[-(Trp-d-Leu)4-Gln-d-Leu-] rings embedded in DMPC lipid bilayers was examined using all-atom molecular dynamics (AAMD) simulations. Two conformational isomers of ß-d-glucose, equatorial (4C1) and axial (1C4) chair conformers, were used to examine conformational effects on the hydrogen bond network, energetics, and diffusivity of glucose transport through the CPN. Calculations of the number of hydrogen bonds of the two glucose conformers with water molecules and with the CPN illustrate that the total number of hydrogen bonds of the conformers decreases inside the channel compared to bulk water due to the confinement characteristics of the interior of the CPNs although new hydrogen bonds between the hydroxyl and hydroxymethyl hydrogens of glucose and the carbonyl oxygens in the CPN backbone are formed. Despite the decrease of the number of hydrogen bonds inside the CPN, intramolecular hydrogen bonds of 1C4 are maintained during permeation of 1C4 through the CPN. The retention of intramolecular hydrogen bonds and the spherical shape of 1C4 give rise to considerably weaker orientational preferences and higher diffusion coefficients for 1C4 than those of 4C1 inside and outside the CPN. Due to larger dipole moments induced by the alignment of hydroxyl and hydroxymethyl groups, 1C4 has more favorable interactions with the CPN backbone at the channel entrances and inside the channel than 4C1. In the middle of the CPN channel, entropic gains originating from higher orientational and translational degrees of freedom of 1C4 than those of 4C1 also contribute to lower free energy wells for 1C4 inside the CPN. This work reveals that the conformational variation and intramolecular hydrogen bond formation of ß-d-glucose can have important effects on the energetics and dynamics of glucose transport through CPNs, providing insight into the translocation mechanism of d-glucose into the cell through glucose transporters (GLUTs) and the dynamics of glucose confined in silica nanochannels. It is also demonstrated that CPNs can indeed facilitate the permeation of small hydrophilic molecules such as glucose and can be utilized as a novel carrier system for hydrophilic drug compounds into the cell.

Energetic and Dynamic Analysis of Transport of Na+ and K+ through a Cyclic Peptide Nanotube in Water and in Lipid Bilayers.

Potential of mean force (PMF) profiles and position-dependent diffusion coefficients of Na+ and K+ are calculated to elucidate the translocation of ions through a cyclic peptide nanotube, composed of 8 × cyclo[-(d-Leu-Trp)4-] rings, in water and in hydrated DMPC bilayers. The PMF profiles and PMF decomposition analysis for the monovalent cations show that favorable interactions of the cations with the CPN as well as the lipid bilayer and dehydration free energy penalties are two major competing factors which determine the free energy surface for ion transport through CPNs both in water and in lipid bilayers, and that the selectivity of CPNs to cations mainly arises from favorable interaction energies of cations with CPNs and lipid bilayers that are more dominant than the dehydration penalties. Calculations of the position-dependent diffusion coefficients and dynamic friction kernels of the cations indicate that the dehydration process along with the molecular rearrangements occurring outside the channel and the coupling of the ion motions with the chain-structured water movements inside the channel lead to a decrease of the diffusion coefficients far away from the channel entrance and also reduced coefficients inside the channel. The PMF and diffusivity profiles for Na+ and K+ reveal that the energetics of ion transport through the CPN are governed by global interactions of ions with all the components in the system, while the diffusivity of ions through the channel is mostly determined by local interactions of ions with the confined water molecules inside the channel. Comparison of Na+ and K+ ion distributions based on overdamped Brownian dynamics simulations based on the PMF and diffusivity profiles with the corresponding results from molecular dynamics shows good agreement, indicating accuracy of the Bayesian inference method for determining diffusion coefficients in this application. In addition, this work shows that position-dependent diffusion coefficients of ions are required to explain the dynamics and conductance of ions through the CPN properly.