Potential Of Mean Force Curves Research Articles

Permeability of Dermatological Solutes through the Short Periodicity Phase of Human Stratum Corneum Lipid Bilayers.

Determining the permeability of drug-like solutes through the densely packed and heterogeneous stratum corneum lipid layer presents a significant challenge. In this study, we employed umbrella sampling with a periodic weighing function applied to the center of mass of the lipid bilayers. Precise umbrella sampling was conducted with an interframe distance of 0.5 Å, spanning from the bilayer center to the water phase, and each frame was simulated for at least 20 ns. Autocorrelation functions, potential of mean force (PMF), and diffusivity profiles were analyzed for six solutes (testosterone, benzene, caffeine, ethanol, mannitol, and histidine). The results revealed that autocorrelations were dependent solely on the medium, whether water or lipid phase. Diffusivity and PMF profiles along the reaction coordinate were influenced by the hydrophilicity of the solute rather than its size. For hydrophobic solutes, the PMF curves exhibited a minimum at the bilayer center, while for hydrophilic solutes, the PMFs peaked at the bilayer center and lipid tails (where the lipid tails are not interacting with the cholesterol). Diffusivity curves were low at the bilayer center and water phase, with peaks observed at the headgroup or the boundary between fatty acid and cholesterol (1 nm from the bilayer center). The quantitative findings presented in this work hold significance for pharmacists and drug designers.

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.

Contact angle and stability of interfacial nanobubble supported by gas monolayer

Since solid-liquid interfacial nanobubbles (INBs) were first imaged, their long-term stability and large contact angle have been perplexing scientists. This study aimed to investigate the influence of internal gas density and external gas monolayers on the contact angle and stability of INB using molecular dynamics simulations. First, the contact angle of a water droplet was simulated at different nitrogen densities. The results showed that the contact angle increased sharply with an increase in nitrogen density, which was mainly caused by the decrease in solid-gas interfacial tension. However, when the nitrogen density reached 2.57 nm−3, an intervening gas monolayer (GML) was formed between the solid and water. After the formation of GML, the contact angle slightly increased with increasing gas density. The contact angle increased to 180° when the nitrogen density reached 11.38 nm−3, indicating that INBs transformed into a gas layer when they were too small. For substrates with different hydrophobicities, the contact angle after the formation of GML was always larger than 140° and it was weakly correlated with substrate hydrophobicity. The increase in contact angle with gas density represents the evolution of contact angle from macro- to nano-bubble, while the formation of GML may correspond to stable INBs. The potential of mean force curves demonstrated that the substrate with GML could attract gas molecules from a longer distance without the existence of a potential barrier compared with the bare substrate, indicating the potential of GML to act as a gas-collecting panel. Further research indicated that GML can function as a channel to transport gas molecules to INBs, which favors stability of INBs. This research may shed new light on the mechanisms underlying abnormal contact angle and long-term stability of INBs.

Interaction of lignin dimers with model cell membranes: A quartz crystal microbalance and molecular dynamics simulation study.

A study of the interaction between cell membranes and small molecules derived from lignin, a protective phenolic biopolymer found in vascular plants, is crucial for identifying their potential as pharmacological and toxicological agents. In this work, the interactions of model cell membranes [supported 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayers] are compared for three βO4 dimers of coniferyl alcohol (G lignin monomer): guaiacylglycerol guaiacol ester with a hydroxypropenyl (HOC3H4-) tail (G-βO4'-G), a truncated GG dimer without HOC3H4- (G-βO4'-truncG), and a benzylated GG dimer (benzG-βO4'-G). The uptake of the lignin dimers (per mass of lipid) and the energy dissipation (a measure of bilayer disorder) are higher for benzG-βO4'-G and G-βO4'-truncG than those for G-βO4'-G in the gel-phase DPPC bilayer, as measured using quartz crystal microbalance with dissipation (QCM-D). A similar uptake of G-βO4'-truncG is observed for a fluid-phase bilayer of 1,2-dioleoyl-sn-glycero-3-phosphocholine, suggesting that the effect of the bilayer phase on dimer uptake is minimal. The effects of increasing lignin dimer concentration are examined through an analysis of density profiles, potential of mean force curves, lipid order parameters, and bilayer area compressibilities (disorder) in the lipid bilayers obtained from molecular dynamics simulations. Dimer distributions and potentials of mean force indicate that the penetration into bilayers is higher for benzG-βO4'-G and G-βO4'-truncG than that for G-βO4'-G, consistent with the QCM-D results. Increased lipid tail disorder due to dimer penetration leads to a thinning and softening of the bilayers. Minor differences in the structure of lignin derivatives (such as truncating the hydroxypropenyl tail) have significant impacts on their ability to penetrate lipid bilayers.

Voltage-gated multilayer graphene nanochannel for K+/Na+ separation: A molecular dynamics study

Biological protein channels have a series of remarkable properties such as selective ion or water transport. In this work, using molecular dynamics simulations, a bioinspired flexible graphene nanochannel were designed based on the structures and mechanisms of biological K+ channel. The results show that the graphene nanochannel stacked from six graphene nanopores with four carbonyl groups attached at the edges of each pore presents a voltage-gated K+/Na+ separation. As the increase of voltage bias, the separation performance first increases and then decreases. The potential of mean force curves for K+ and Na+ indicate that the energy barrier for K+ transport is smaller due to the easier dehydration of K+, which results in its higher ion current. Meanwhile, the hydration structures of the passing ions under different electric field intensities show that the transport of K+ through dihydrate is more efficient, which leads to the higher separation ratio. In addition, self-driven and Coulomb knock-on ion transport mechanisms are revealed. These findings provided here deepen our understanding about the mechanism of selectively ion transport in biological ion channels, and also give a general scheme for the design of flexible nanochannels that can be used in ion sensors, nanofiltration, and other related voltage-gated nanofluidic devices.

T7 RNA Polymerase Discriminates Correct and Incorrect Nucleoside Triphosphates by Free Energy

RNA polymerase (RNAP) is the primary machine responsible for transcription. Its ability to distinguish between correct (cognate) and incorrect (noncognate) nucleoside triphosphates (NTPs) is important for fidelity control in transcription. In this work, we investigated the substrate selection mechanism of T7 RNAP from the perspective of energetics. The dissociation free energies were determined for matched and unmatched base pairs in the preinsertion complex using the umbrella sampling method. A clear hydrogen-bond-rupture peak is observed in the potential of mean force curve for a matched base pair, whereas no such peaks are present in the position of mean force profiles for unmatched ones. The free-energy barrier could prevent correct substrates from being separated from the active site. Therefore, when NTPs diffuse into the active site, correct ones will stay for chemistry once they establish effective base pairing contacts with the template nucleotide, whereas incorrect ones will be withdrawn from the active site and rejected back to solution. This result provides an important energy evidence for the substrate selection mechanism of RNAP. Then we elucidated energetics and molecular details for correct NTP binding to the active site of the insertion complex. Our observations reveal that strong interactions act on the triphosphate of NTP to constrain its movement, whereas relatively weak interactions serve to position the base in the correct conformation. Triple interactions, hydrophobic contacts from residues M635 and Y639, base stacking from the 3′ RNA terminal nucleotide, and base pairing from the template nucleotide act together to position the NTP base in a catalytically competent conformation. At last, we observed that incorrect NTPs cannot be as well-stabilized as the correct one in the active site when they are misincorporated in the insertion site. It is expected that our work can be helpful for comprehensively understanding details of this basic step in genetic transcription.

Toward High-Throughput Computational Screening of Carbon Nanotube Solvents

We use the corresponding distances method (CDM) to computationally assess the quality of 10 experimentally tested carbon nanotube (CNT) solvents. The CDM produces accurate and high-resolution potential of mean force curves from a single simulation per solvent. The method's very high efficiency allows us to investigate an unprecedented number of solvents in one study. The simulation results indicate that none of the tested molecules are solvents in the thermodynamic sense; instead, they are dispersants preventing reaggregation of already dispersed CNTs. We find that the dispersion free energy barrier correlates very well with the experimentally measured performance of the dispersants; i.e., the simulations place the solvents in the correct performance order. Our analysis of the structure-function relationship rationalizes this order.

Replacement of Oxygen by Sulfur in Small Organic Molecules. 2. Theoretical Studies on the Tautomeric Equilibria of the 5-OH Substituted Oxazole, Thiazole, Isoxazole, and Isothiazole in the Isolated State and in Solution

Heterocycles are frequently appearing structure-building elements in drug candidates. The present paper investigates the consequences of the replacement of the oxygen atom by a sulfur atom in the isomeric rings of 5OH-oxazole and 5OH-isoxazole. Theoretical calculations at the B97D/aug-cc-pvqz level (with five additional “d” functions on the S atom) and considering the CCSD(T) level at the complete basis set limit followed the structural and concomitant free energy changes for the four title molecules in the isolated state, and in dichloromethane and water solvents. The selected species are subject to both conformational and tautomeric transformations. The polarizable continuum method (PCM) was applied for in-solution geometry optimization and estimation of the free energy components. In addition, explicit solvent Monte Carlo simulations were performed to calculate the relative solvation free energies of selected tautomers. This latter method allows for presenting solute atom - solvent atom radial distribution functions and the estimation of the number solute-solvent hydrogen bonds. The tautomeric preferences for the oxygen and sulfur containing species, which are sometimes different, were discussed and the calculated results were compared with experimental measurements for the structure composition available for 5OH-isoxazole and its methyl derivatives of in water. Potential of mean force curves were calculated for the 5-one tautomers of 5OH-isothiazole in dichloromethane and the possible tautomeric pathways for this solute in a non-protic solvent was discussed. Keywords: Conformational/tautomeric equilibria, Monte Carlo, PCM, potential of mean force, solution structure, tautomerization mechanism.

Relationships between Mechanostability, Aggregation Rate and Binding Affinity of Peptides: Insights from All-ATOM Modeling in Explicit Solvent

Fibril formation resulting from protein misfoding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite much progress in understanding the protein/peptide aggregation process, the factors governing aggregation rates and stability of oligomers/fibrils have not been fully understood. Studying the oligomerization of FVFLM peptides from the placenta of Preeclampsia patients and from using all-atom molecular dynamics simulations with GROMOS43a1 force field and explicit water, we show that fibril formation time (mechanical stability) strongly correlates with binding affinity. The faster fibril formation time (stronger mechanical stability) the stronger binding. The extent of superior mechanical stability/binding of FVFLM as compared to KLVFF, was quantified by subjecting both to steered molecular dynamics. The binding free energy of FVFLM and KLVFF systems, calculated from potential of mean force curve obtained through extensive umbrella sampling simulations, clearly established FVFLM as a better binder than KLVFF. Our study indicates that oligomer formation times are strongly correlated with binding energy, the faster the aggregation rate of peptide the stronger has been noted to be its mechanical stability and binding affinity.

Free Energy Calculation for Base Pair Dissociation in a DNA Duplex

DNA is the main genetic material for living organisms including many viruses. DNA duplex, coded with A=T and G=C base pairs, is well suited for biological information storage. The interactions between two bases in a base pair contribute to the stability of DNA duplex, and are further related to gene replication and transcription. In this study, we use all-atom Molecular dynamics (MD) simulations combined with Umbrella sampling (US) method to determine the free energy profiles and explore the molecular details for base pair dissociations. Four groups of DNA duplexes with different sequences have been constructed and a total of 4.3 mu s MD simulations have been carried out. In the potential of mean force (PMF) profile for G equivalent to C base pair dissociation (denoted as PMF-PGC), we observed three peaks, which correspond to the three moments G equivalent to C base pair loses its three hydrogen bonds respectively. Differently, A=T base pair loses its two hydrogen bonds within a very short time. As a result, only one hydrogen bond rupture peak was observed in its PMF curve (denoted as PMF-PAT). Compared with PMF-PAT, the overall free energy barrier in PMF-PGC is higher, which is due to the better stability of G equivalent to C than A=T. In the latter sections of both PMFs, free energies are still increasing, which is mainly resulted from the rigidity of DNA duplex backbone. We have also investigated the impact of neighboring base pairs on the stability of middle one. It is found that neighboring G equivalent to C base pairs increase the stability of A=T base pair while neighboring C equivalent to G base pairs reduce the stability of A=T base pair. Additionally, neighboring T=A base pairs have little influence on the stability of A=T base pair.

Different ways of looking at the force between two nanocrystals.

The potential of mean force (PMF) between two nanocrystals (NCs) represents an effective interaction potential that is essential when explaining the assembly of NCs to superstructures. For a given temperature, the PMF is obtained best from molecular dynamics simulations. Based on a density functional approach, this study proposes three methods of predicting the PMF for any given temperature based on a single molecular dynamics simulation for one temperature. The three methods construct the PMF by considering the ligands as an ideal gas, as hard-sphere chains, or as Lennard-Jones interaction sites. To apply this methodology, the density of the interaction centers must be extracted from the simulation data. For the ideal gas model, a straightforward sampling procedure with a fixed lattice in space leads to free energies that are too large in order to consistently explain the simulation data for different temperatures. Naive sampling does not account for the small momenta added to the NCs when coupled to a thermostat. A method is proposed that corrects for the unphysical steps during the simulation. The ideal gas contribution computed for the corrected density is significantly smaller than the one obtained from naive sampling and can thus explain the temperature dependence of the PMF correctly. For the hard-sphere chain model, where a weighted density is used, the correction of the particle density is not essential. However, the PMF calculated based on the corrected density confirms our approach. All three models predict PMF curves in very good agreement with simulation results, but they differ in the number of input parameters and the computational effort. Based on the modeling results, we predict the existence of an additional attractive force at small distances of the NCs - a depletion force.

Transferability and nonbond functional form of coarse grained force field - tested on linear alkanes.

Whether or not a coarse grained force field (CGFF) can be made to be transferrable is an important question to be addressed. By comparing potential energy with potential of mean force (PMF) of a molecular dimer, we proposed to use a free energy function (FE-12-6) with the parameters in entropic and energetic terms explicitly to represent the nonbond interactions in CGFF. Although the FE-12-6 function cannot accurately describe the PMF curves, a cancelation of short radii and strong repulsion makes the function a good approximation. For nonpolar molecules represented by linear alkanes, FE-12-6 is demonstrated to be highly effective in representing the nonbond interactions in CGFF. The force field parameters are well transferrable among different alkane molecules, in different thermodynamic states and for predicting various thermodynamic properties including heats of vaporization, vapor-liquid-equilibrium coexistence curves, surface tensions, and liquid densities.

Do Drugs Have Access to the P-Glycoprotein Drug-Binding Pocket through Gates?

The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction coordinate obtained with the WHAM approach were similar, with no activation energy required for crossing the gate. Moreover, drug transit from bulk water into the DBP was characterized as an overall free-energy downhill process.

Structure Simulations of Solutions with Small Organic Solutes at Ambient Temperature and pH =7

This review surveys mainly recent computer simulations for exploring the structure of solutions with small organic solutes in water and organic solvents. The solute’s geometry may be optimized at a high quantum mechanical level if some polarizable continuum-solvent method is utilized and then kept constant throughout subsequent simulations. In-solution geometry optimization is especially important in cases where only the environment stabilizes the structure, e.g., the zwitterionic form for amino acids in water. For solutes subject to conformational/tautomeric equilibria separate modeling is needed if rigid geometries are considered. In contrast, finding adequate intramolecular force-field parameters for torsional potentials, non-bonded van der Waals interactions and consideration of the electrostatic-potential-derived net atomic charges through the calculation of the Coulombic interactions are key issues in molecular dynamics simulations with flexible solute geometries. Furthermore, relative conformational energies can change greatly depending on the solvent and/or protein/membrane environment, thus the applied force-field has to account for their effects. Proper choice for the protonation state of acidic or basic solutes and assuring the required concentration are important simulation conditions, as well, for obtaining relevant models. The solution structures could be ultimately characterized by calculating different distribution functions and applying specifically developed statistics. Potential of mean force curves usefully follow the free energy changes through solute dimerization. Results of experimental studies using different spectroscopic and diffraction methods have been compared with those from theoretical simulations. Keywords: Conformers, force fields, hydrogen bonds, molecular dynamics, Monte Carlo, solute and solvent modeling, structure statistics, tautomers.

Molecular dynamics simulation of a cucurbituril based molecular switch triggered by pH changes

Molecular Dynamics (MD) simulations are performed for a cucurbituril-pseudorotaxane system that functions as a molecular switch in which the movement of the macrocycle (CB) component of the rotaxane between two sites is triggered by an appropriate change in pH. The system consists of a CB bead and a fluorenyltriamine string in aqueous solution. Examining the extracted snapshots reveals that the fluorenyl ring bends toward the CB rim when it locates at the butyl moiety, and it becomes aligned with the rest of the guest when it locates at the hexyl moiety. No movement of the macrocycle between the possible positions for CB6 complexes for the fully protonated or the diprotonated guests was observed during the 20ns simulation. However, such movement was observed in the case of CB7 and CB8. Umbrella sampling was used to obtain the potential of mean force curves, which demonstrates the existence of an energy barrier between the two sites. The height of the barrier was found to decrease as the size of the CB increases. Molecular Mechanics Poisson–Boltzmann Surface Area results indicate that the host–guest electrostatic interactions have the largest contribution to the stability of the complexes.

Theoretical in-Solution Conformational/Tautomeric Analyses for Chain Systems with Conjugated Double Bonds Involving Nitrogen(s).

Conformational/tautomeric transformations for X=CH–CH=Y structures (X = CH2, O, NH and Y = NH) have been studied in the gas phase, in dichloromethane and in aqueous solutions. The paper is a continuation of a former study where s-cis/s-trans conformational equilibria were predicted for analogues. The s-trans conformation is preferred for the present molecules in the gas phase on the basis of its lowest internal free energy as calculated at the B97D/aug-cc-pvqz and CCSD(T)CBS (coupled-cluster singles and doubles with non-iterative triples extrapolated to the complete basis set) levels. Transition state barriers are of 29–36 kJ/mol for rotations about the central C–C bonds. In solution, an s-trans form is still favored on the basis of its considerably lower internal free energy compared with the s-cis forms as calculated by IEF-PCM (integral-equation formalism of the polarizable continuum dielectric solvent model) at the theoretical levels indicated. A tetrahydrate model in the supermolecule/continuum approach helped explore the 2solute-solvent hydrogen bond pattern. The calculated transition state barrier for rotation about the C–C bond decreased to 27 kJ/mol for the tetrahydrate. Considering explicit solvent models, relative solvation free energies were calculated by means of the free energy perturbation method through Monte Carlo simulations. These calculated values differ remarkably from those by the PCM approach in aqueous solution, nonetheless the same prevalent conformation was predicted by the two methods. Aqueous solution structure-characteristics were determined by Monte Carlo. Equilibration of conformers/tautomers through water-assisted double proton-relay is discussed. This mechanism is not viable, however, in non-protic solvents where the calculated potential of mean force curve does not predict remarkable solute dimerization and subsequent favorable orientation.

Physics-Based Potentials for Coarse-Grained Modeling of Protein-DNA Interactions.

Physics-based potentials have been developed for the interactions between proteins and DNA for simulations with the UNRES + NARES-2P force field. The mean-field interactions between a protein and a DNA molecule can be divided into eight categories: (1) nonpolar side chain–DNA base, (2) polar uncharged side chain–DNA base, (3) charged side chain–DNA base, (4) peptide group–phosphate group, (5) peptide group–DNA base, (6) nonpolar side chain–phosphate group, (7) polar uncharged side chain–phosphate group, and (8) charged side chain–phosphate group. Umbrella-sampling molecular dynamics simulations in explicit TIP3P water using the AMBER force field were carried out to determine the potentials of mean force (PMF) for all 105 pairs of interacting components. Approximate analytical expressions for the mean-field interaction energy of each pair of the different kinds of interacting molecules were then fitted to the PMFs to obtain the parameters of the analytical expressions. These analytical expressions can reproduce satisfactorily the PMF curves corresponding to different orientations of the interacting molecules. The results suggest that the physics-based mean-field potentials of amino acid–nucleotide interactions presented here can be used in coarse-grained simulation of protein–DNA interactions.

Hybrid Steered Molecular Dynamics Approach to Computing Absolute Binding Free Energy of Ligand–Protein Complexes: A Brute Force Approach That Is Fast and Accurate

Computing the free energy of binding a ligand to a protein is a difficult task of essential importance for which purpose various theoretical/computational approaches have been pursued. In this paper, we develop a hybrid steered molecular dynamics (hSMD) method capable of resolving one ligand–protein complex within a few wall-clock days with high enough accuracy to compare with the experimental data. This hSMD approach is based on the relationship between the binding affinity and the potential of mean force (PMF) in the established literature. It involves simultaneously steering n (n = 1, 2, 3, ...) centers of mass of n selected segments of the ligand using n springs of infinite stiffness. Steering the ligand from a single initial state chosen from the bound state ensemble to the corresponding dissociated state, disallowing any fluctuations of the pulling centers along the way, one can determine a 3n-dimensional PMF curve connecting the two states by sampling a small number of forward and reverse pulling paths. This PMF constitutes a large but not the sole contribution to the binding free energy. Two other contributors are (1) the partial partition function containing the equilibrium fluctuations of the ligand at the binding site and the deviation of the initial state from the PMF minimum and (2) the partial partition function containing rotation and fluctuations of the ligand around one of the pulling centers that is fixed at a position far from the protein. We implement this hSMD approach for two ligand–protein complexes whose structures were determined and whose binding affinities were measured experimentally: caprylic acid binding to bovine β-lactoglobulin and glutathione binding to Schistosoma japonicum glutathione S-transferase tyrosine 7 to phenylalanine mutant. Our computed binding affinities agree with the experimental data within a factor of 1.5. The total time of computation for these two all-atom model systems (consisting of 96K and 114K atoms, respectively) was less than one wall-clock week using 512 cores (32 Xeon E5-2680 processors).

Structure based computational assessment of channel properties of assembled ORF-8a from SARS-CoV.

ABSTRACTORF 8a is a short 39 amino acid bitopic membrane protein encoded by severe acute respiratory syndrome causing corona virus (SARS‐CoV). It has been identified to increase permeability of the lipid membrane for cations. Permeability is suggested to occur due to the assembly of helical bundles. Computational models of a pentameric assembly of 8a peptides are generated using the first 22 amino acids, which include the transmembrane domain. Low energy structures reveal a hydrophilic pore mantled by residues Thr‐8, and −18, Ser‐11, Cys‐13, and Arg‐22. Potential of mean force (PMF) profiles for mono (Na+, K+, Cl−) and divalent (Ca2+) ions along the pore are calculated. The data support experimental findings of a weak cation selectivity of the channel. Calculations on 8a are compared to data derived for a pentameric bundle consisting of the M2 helices of the bacterial pentameric ligand gated ion channel GLIC (3EHZ). PMF curves of both, bundles 8a and M2, show sigmoidal shaped profiles. In comparison to the data for the M2‐GLIC model, data of the 8a bundle show lower amplitude of the PMF values between maximum and minimum and less discrimination amongst ions. Proteins 2015; 83:300–308. © 2014 Wiley Periodicals, Inc.

Competing intramolecular vs. intermolecular hydrogen bonds in solution.

A hydrogen bond for a local-minimum-energy structure can be identified according to the definition of the International Union of Pure and Applied Chemistry (IUPAC recommendation 2011) or by finding a special bond critical point on the density map of the structure in the framework of the atoms-in-molecules theory. Nonetheless, a given structural conformation may be simply favored by electrostatic interactions. The present review surveys the in-solution competition of the conformations with intramolecular vs. intermolecular hydrogen bonds for different types of small organic molecules. In their most stable gas-phase structure, an intramolecular hydrogen bond is possible. In a protic solution, the intramolecular hydrogen bond may disrupt in favor of two solute-solvent intermolecular hydrogen bonds. The balance of the increased internal energy and the stabilizing effect of the solute-solvent interactions regulates the new conformer composition in the liquid phase. The review additionally considers the solvent effects on the stability of simple dimeric systems as revealed from molecular dynamics simulations or on the basis of the calculated potential of mean force curves. Finally, studies of the solvent effects on the type of the intermolecular hydrogen bond (neutral or ionic) in acid-base complexes have been surveyed.