Computational Characterization of the Role of LEM2/LaminA Interactions on the Stability of BAF-Dimer Using Molecular Simulations.

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.

Potential of mean force (PMF) profiles of a single Na+ or K+ ion passing through a cyclic peptide nanotube, cyclo[-(D-Ala-Glu-D-Ala-Gln)2-], in water are calculated to provide insight into ion transport and to understand the conductance difference between these two ions. The PMF profiles are obtained by performing steered molecular dynamics (SMD) simulations that are based on the Jarzynski equality. The computed PMF profiles for both ions show barriers of around 2.4 kcal/mol at the channel entrances and exits and energy wells in the middle of the tube. The energy barriers, so-called dielectric energy barriers, arise due to the desolvation of water molecules when ions move across the nanotube, and the energy wells appear as a result of attractive interactions between the cations and negatively charged carbonyl oxygens on the backbone of the tube. We find more and deeper energy wells in the PMF profile for Na+ than for K+, which suggests that Na+ ions have a longer residence time inside the nanotube and that permeation of Na+ ions is reduced compared to K+ ions. Calculations of the radial distribution functions (RDF) between the ions and oxygens in the water molecules and in carbonyl groups on the tube and an investigation of the orientations of the carbonyl groups show that, in contrast with the dynamic carbonyl groups observed in the selectivity filter of the KcsA ion channel, the carbonyl groups in the cyclic peptide nanotube are relatively rigid, with only slight reorientation of the carbonyl groups as the cations pass through. The rigidity of the carbonyl groups in the cyclic peptide nanotube can be attributed to their role in hydrogen bonding, which is responsible for the tube structure. Comparison of the PMF profiles with the electrostatic energy profiles calculated from the Poisson-Boltzmann (PB) equation, a dielectric continuum model, reveals that the dielectric continuum model breaks down in the confined region within the tube that governs ion transport.

Oriented attachment (OA) of nanoparticles is an important crystal growth pathway in the synthesis of hierarchical structures. Although a significant understanding of OA has been made, the effect of atomistic misalignment and the roles of solvent/particle and particle/particle interactions on the structure–energy relationship during an OA remain elusive. In this study, we perform molecular dynamics simulations to calculate the potential of mean force (PMF) profile for gibbsite particle translation on a gibbsite slab with 1 or 2 intervening water layers (1W or 2W). The structures of the gibbsite surfaces and the confined water are analyzed to determine how the number and type of hydrogen bonds (H-bonds) influence the free energy profile during the translation. The PMF profile exhibits a periodicity of length 5.078 Å, consistent with the gibbsite unit cell size along the translation direction. The changes in the surface–water and water–water hydrogen bond network and water and surface OH groups’ orientations during the translation are strongly coupled with the changes in the PMF profile in the 1W case. However, when increasing the number of intervening water layers from 1W to 2W, the particle/slab misalignment becomes a dominant factor controlling the behavior of the PMF profile. We also establish a method to quantify misalignment between the particle and the slab, which exhibits a strong correlation with the free energy for the 2W case. These results shed more light into the roles of particle/slab misalignment and hydrogen bond network in the OA of mineral particles in aqueous solution.

Molecular dynamics simulations of wild type and two mutant (T248F and L251T) human [Formula: see text]7 nicotinic acetylcholine receptors (nAChR) have been performed. The channel transmembrane domains were modeled from the closed channel structure from torpedo ray (PDB ID 2BG9) and embedded in DPPC lipid bilayers, surrounded by physiological saline solution. An external electric field was used to obtain stable open channel structures. The adaptive biasing force (ABF) method was used to obtain potential of mean force (PMF) profiles for Na[Formula: see text] ion translocation through the wild type and mutant receptors. Based on the geometry and PMF profiles, the channel gate was found to be at one of the two hydrophobic conserved regions (V249-L251) near the lower end of the channel. The L251T mutation reduced the energetic barrier by 1.9[Formula: see text]kcal/mol, consistent with a slight increase in the channel radius in the bottleneck region. On the other hand, the T248F mutation caused a significant decrease in the channel radius (0.4 Å) and a substantial increase of 3.9[Formula: see text]kcal/mol in the energetic barrier. Ion permeation in all three structures was compared and found to be consistent with barrier height values. Using an external field in an incrementally increasing manner was found to be an effective way to obtain stable open, conducting channel structures.

Computing free energies of complex biomolecular systems via atomistic (AT) molecular dynamics (MD) simulations remains a challenge due to the need for adequate sampling and convergence. Recent coarse-grained (CG) methodology allows simulations of significantly larger systems (∼10(6) to 10(8) atoms) over longer (μs/ms) time scales. Such CG models appear to be capable of making semiquantitative predictions. However, their ability to reproduce accurate thermodynamic quantities remains uncertain. We have recently used CG MD simulations to compute the potential of mean force (PMF) or free energy profile of a small peptide toxin interacting with a lipid bilayer along a 1D reaction coordinate. The toxin studied was VSTx1 (Voltage Sensor Toxin 1) from spider venom which inhibits the archeabacterial voltage-gated potassium (Kv) channel KvAP by binding to the voltage-sensor (VS) domains. Here, we re-estimate this PMF profile using (i) AT MD simulations with explicit membrane and solvent and (ii) an implicit membrane and solvent (generalized Born; GBIM) model where only the peptide was explicit. We used the CG MD free energy simulations to guide the setup of the corresponding AT MD simulations. The aim was to avoid local minima in the AT simulations which would be difficult over shorter AT time scales. A cross-comparison of the PMF profiles revealed a conserved topology, although there were differences in the magnitude of the free energies. The CG and AT simulations predicted a membrane/water interface free energy well of -27 and -23 kcal/mol, respectively (with respect to water). The GBIM model, however, gave a reduced interfacial free energy well (-12 kcal/mol). In addition, the CG and GBIM models predicted a free energy barrier of +61 and +96 kcal/mol, respectively, for positioning the toxin at the center of the bilayer, which was considerably smaller in the AT simulations (+26 kcal/mol). Thus, we present a framework for serially combining CG and AT simulations to estimate the free energy of peptide/membrane interactions. Such approaches for combining simulations at different levels of granularity will become increasingly important in future studies of complex membrane/protein systems.

Physical confinement of polymers not only affects their structure but also modifies their effective interaction profiles. In this article, we investigate the nature of graphene-adsorbed poly(amidoamine) (PAMAM) dendrimers' interactions using fully atomistic molecular dynamics simulations. Using the umbrella sampling technique, we calculate the potential of mean force (PMF) profiles for the interaction between two graphene-adsorbed PAMAM dendrimers of generations 3 and 4 as a function of their protonation levels. We find that the attractive PMF profile observed for the interaction between two nonprotonated (high pH) PAMAM dendrimers in bulk becomes repulsive upon adsorption. Also, the repulsive interdendrimer interactions known in bulk for the protonated dendrimers become enhanced for the adsorbed case. We further explain these weakened interactions by explicitly showing that the dendrimer-graphene interaction is an order of magnitude larger than the dendrimer-dendrimer bulk interaction. Using the force integration method, we obtain the contributions from various subinteractions present in the system, that is, dendrimer-water, dendrimer-ions, dendrimer-graphene, and dendrimer-dendrimer to the total PMF. From these contributions, we conclude that the reduced dendrimer-dendrimer interactions in the adsorbed case, as compared to those in bulk, lead to the enhanced repulsive effective interdendrimer interactions. Our PMF profiles fit well with the sum of exponential and Gaussian functions, proposed in the bulk interdendrimer interaction study. We hope the current results provide the microscopic origin of how adsorption weakens the interpolymer interactions in general.

Autodissociation in liquid water is one of the most important processes in various topics of physical chemistry, such as acid-base chemistry. Molecular simulations have elucidated most of the molecular mechanisms at the atomic level, yet quantitative analysis to compare with experiments using the potential of mean force (PMF) remains a hurdle, including the definition of reaction coordinates and the accuracy of liquid structures by ab initio molecular dynamics (AIMD) simulations with density functional theory (DFT) methods. Here, we perform AIMD simulations with the revPBE-D3 exchange-correlation functional to compute the PMF profiles of autoionization, or proton transfer (PT), in liquid water. For the quantitative analysis with physically meaningful reaction coordinates, we employ a PT coordinate, donor-acceptor (OH--H3O+) distance, and hydrogen (H)-bond number. The one-dimensional (1D) PMF profile along the PT coordinate shows no local minimum in the product state of PT (OH- and H3O+), which is necessary to accurately compute the acid dissociation constant (or pKa). On the other hand, the 2D PMF profiles along the PT coordinate and donor-acceptor distance show local minima in the product state and reaction barriers, and the computed pKw is comparable to the experiment. In addition, the 2D PMF profiles along the PT coordinate and the H-bond number reveal the molecular mechanism of the H-bond rearrangement concomitant with PT, in which the H-bond breaking before PT is slightly preferable. These findings indicate that an accurate evaluation of pKa by MD simulations requires the donor-acceptor distance in addition to the conventional PT coordinate.

MDM2 and MDMX are potential targets for p53-dependent cancer therapy. Peptides are key in cellular immunology and oncology, and cyclic peptides generally have higher half-life than their linear counterparts. However, prediction of cyclic peptide–protein binding is challenging with normal molecular simulation approaches because of high peptide flexibility. Here, we used global peptide docking, normal molecular dynamics, Gaussian accelerated molecular dynamics (GaMD), two-dimensional (2D) potential of mean force (PMF) profiles, and solvated interaction energy (SIE) techniques to investigate the interactions of MDM2/MDMX with three N-to-C-terminal cyclic peptide–based inhibitors. We determined the possible cyclic peptide–MDM2/MDMX complex structures via 2D PMF profiles and SIE calculations. Our findings increase the accuracy of peptide–protein structural prediction, which may facilitate cyclic peptide drug design. Advancements in the computational methods and computing power may further aid in addressing the challenges in cyclic peptide drug design. Communicated by Ramaswamy H. Sarma

Unwinding DNA strands by single-walled carbon nanotubes: Molecular docking and MD simulation approach

Formate/nitrite transporters (FNTs) selectively transport monovalent anions and are found in prokaryotes and lower eukaryotes. They play a significant role in bacterial growth and act against the defense mechanism of infected hosts. Because FNTs do not occur in higher animals, they are attractive drug targets for many bacterial diseases. Phylogenetic analysis revealed that they can be classified into eight subgroups, two of which belong to the uncharacterized YfdC-α and YfdC-β groups. Experimentally determined structures of FNTs belonging to different phylogenetic groups adopt the unique aquaporin-like hourglass helical fold. We considered the formate channel from Vibrio cholerae, the hydrosulphide channel from Clostridium difficile, and the uncharacterized channel from Escherichia coli (EcYfdC) to investigate the mechanism of transport and selectivity. Using equilibrium molecular dynamics and umbrella sampling studies, we determined temporal channel radius profiles, permeation events, and potential of mean force profiles of different substrates with the conserved central histidine residue in protonated or neutral form. Unlike the formate channel from V. cholerae and the hydrosulphide channel from C. difficile, molecular dynamics studies showed that the formate substrate was unable to enter the vestibule region of EcYfdC. Absence of a conserved basic residue and presence of acidic residues in the vestibule regions, conserved only in YfdC-α, were found to be responsible for high energy barriers for the anions to enter EcYfdC. Potential of mean force profiles generated for ammonia and ammonium ion revealed that EcYfdC can transport neutral solutes and could possibly be involved in the transport of cations analogous to the mechanism proposed for ammonium transporters. Although YfdC members belong to the FNT family, our studies strongly suggest that EcYfdC is not an anion channel. Absence or presence of specific charged residues at particular positions makes EcYfdC selective for neutral or possibly cationic substrates. Further experimental studies are needed to get a definitive answer to the question of the substrate selectivity of EcYfdC. This provides an example of membrane proteins from the same family transporting substrates of different chemical nature.

Dissecting the Forces that Dominate Dimerization of the Nucleotide Binding Domains of ABCB1

The structure of heterotetrameric sarcosine oxidase (HSO) contains a highly complex system composed of a large cavity and tunnels, which are essential for the reaction and migration of the reactants, products, and intermediates. Previous geometrical analysis using the CAVER program has predicted that there are three possible tunnels, T1, T2, and T3, for the exit pathway of the iminium intermediate, 5-oxazolidinone (5-OXA), of the enzyme reaction. Previous molecular dynamics (MD) simulation of HSO has identified the regions containing the water channels from the density distribution of water. The simulation indicated that tunnel T3 is the most probable exit pathway of 5-OXA. In the present study, the potential of mean force (PMF) for the transport of 5-OXA through tunnels T1, T2, and T3 was calculated using umbrella sampling (US) MD simulations and the weighted histogram analysis method. The PMF profiles for the three tunnels support the notion that tunnel T3 is the exit pathway of 5-OXA, and that 5-OXA tends to stay at the middle of the tunnel. The maximum errors of the calculated PMF for the predicted exit pathway, tunnel T3, were estimated by repeating the US simulations using different sets of initial positions. The PMF profile was also calculated for the transport of glycine within T3. The PMF profiles from the US simulations were in good agreement with the previous predictions that 5-OXA escape through tunnel T3 and how glycine is released to the outside of HSO was discussed.

Potentials of mean force (PMF) are calculated for two model ion pairs in two non-aqueous solvents. Standard non-polarizable molecular dynamics simulation (NPMD) and approximate polarizable simulation (PMD) are implemented and compared as tools for monitoring PMF profiles. For the polar solvent (dimethylsulfoxide, DMSO) the PMF generated in terms of the NPMD reproduces fairly well the refined PMD–PMF profile. For the non-polar solvent (benzene) the conventional NPMD computation proves to be deficient. The validity of the correction found in terms of the approximate PMD approach is verified by its comparison with the result of the explicit PMD computation in benzene. The shapes of the PMF profiles in DMSO and in benzene are quite different. In DMSO, owing to dielectric screening, the PMF presents a flat plot with a shallow minimum positioned in the vicinity of the van der Waals contact of the ion pair. For the benzene case, the observed minimum proves to be unexpectedly deep, which manifests the formation of a tightly-binded contact ion pair. This remarkable effect arises owing to the strong electrostatic interaction that is incompletely screened by a non-polar medium. The PMFs for the binary benzene/DMSO mixtures display intermediate behaviour depending on the DMSO content.

Particle agglomeration is relevant to numerous industrial applications and consumer products. The present work explores interactions between and agglomeration of gamma (γ)-alumina nanoparticles in pure water and dilute aqueous salt solutions. To characterize surface- and salt-specific effects, potential of mean force (PMF) profiles between γ-alumina surfaces ([110] and [100] facets) are extracted using classical molecular dynamics (MD) simulations. Supporting experiments are conducted using dynamic light scattering (DLS) to investigate agglomeration at the macroscale. The ion pairs considered are sodium chloride, ammonium acetate, barium nitrate, and barium acetate; sampling a broad range of the Hofmeister series. As particle surfaces approach contact, free-energy fluctuations of the PMF profiles reflect structural adjustments of the intervening aqueous phase. We extract values for the cohesive energy from the MD results, and parse the resultant effective pair interactions into van der Waals and electrostatic contributions. Molecular scale findings from simulations correlate with hydrodynamic radii of γ-alumina nanoparticles, obtained from DLS experiments. The results highlight the applicability of molecular simulations to identify the origins of macroscale observables.

The behavior of confined water molecules in C-S-H has a great influence on various physical and chemical properties of C-S-H gel, which further determine the macroscale behavior of cement-based materials such as creep, shrinkage, and cracking. Here, using molecular simulations, we investigate the effect of relative humidity (RH) on the behavior of C-S-H at the molecular scale taking as reaction path the interlayer distance (spanning interlayer pores up to small gel pores). The confining pressures, desorption isotherm, the potential of mean force (PMF), stable basal spacings, meta-stable domains, elastic modulus perpendicular to the pore surface, and cavitation of nano-confined water are analyzed. We evaluate these properties as a function of interlayer distance at various RH, ranging from (liquid) saturated (RH = 100%) to completely dried (RH = 0%) conditions at ambient temperature (300 K). From the PMF profiles and pressure isotherms, we can identify equilibrium basal spacings and meta-stable domains. We observe that the stable basal spacing decreases when the RH decreases, therefore interlayer pore shrinkage contributes to drying shrinkage of cement-based materials. We also show that cavitation of water in small C-S-H interlayer spaces is pore size-dependent. Each of these properties can be useful to explain the physical origins of the thermo-hygro-mechanical behavior of cement-based materials and provide a methodology to improve the performance of these materials.KeywordsC-S-HDesorptionGrand canonical Monte Carlo simulationsMolecular dynamicsDisjoining pressureCavitationHydration states