Partitioning Free Energies Research Articles

Spectroscopic insights for the enhanced partitioning and removal of Reactive Violet 5 by mixed micellar formulations under optimized conditions: An ionic-nonionic mechanistic approach

This study demonstrates MEUF (micellar enhanced ultrafiltration) as an effective method for the removal of Reactive Violet 5 (RV5) coming from the synthetic waste. MEUF technique is currently employed to decrease aqueous systems toxicity by employing cationic surfactants micellar media, specifically CPC (cetylpyridinium chloride) and CTAB (Cetyltrimethylammonium bromide). The study also examines the impact of nonionic surfactant on the addition of Triton X-100 (TX-100), on solubilizing capacity of the cationic surfactants. Our goal is to determine the optimal conditions for achieving maximum removal efficiency. RV5 partitioning constant, Kb as well as Gibbs energy of the partition ΔGp determines surfactant and dye molecules interaction. Dye molecules initially interact with ionic surfactants to form ion pairs. Subsequently, these ion pairs become incorporated into micelles and later on can subsequently be removed by MEUFThe maximum values of ΔGp (free energy of partition) were determined to be −42.30 kJmol−1 and −37.15 kJmol−1 using cationic surfactants, CPC and CTAB, respectively. Increase in pollutant size results in easy filtration. This study examines the impact of different factors, such as pH, transmembrane pressure, electrolyte (NaCl), surfactant concentration and revolutions per minute (RPM), on the removal of RV5 from an aqueous system. MEUF efficiency has been evaluated through the determination of permeate flux and rejection percentage values. It has been noticed that both surfactants had the potential to effectively encapsulate RV5. However, overall, the highest R% (rejection percentage) of 97.17% was attained.

Partitioning free energies and induced dipole response of small molecules across a POPC membrane using polarizable molecular dynamics.

The cell membrane is the semi-permeable barrier that regulates flux of materials in and out of the cell. The membrane has a characteristic dielectric gradient due to the amphiphilic nature of its constituent lipids, which have polar head groups and hydrophobic tails. This gradient plays governs many aspects of small-molecule partitioning and membrane protein folding and function. Atomistic details of small-molecule partitioning related to hydration and electronic polarization are still largely unknown. Here, we used polarizable molecular dynamics simulations to understand how the electronic environment influences the process of partitioning. We performed a series of unbiased and umbrella sampling (US) simulations using the Drude polarizable force field (FF) for six different amino-acid sidechain analogs in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. Using a polarizable FF such as Drude allows for the investigation of explicit dipole responses as a function of local electric fields along the membrane normal. We assessed molecular dipole moments, which vary as a function of localization within the membrane, and compared outcomes of the Drude FF simulations to those of the nonpolarizable CHARMM36 FF to investigate the differences in the free energy surfaces of partitioning for our different amino-acid analogs. In doing so, we sought to quantify the effects of using the fixed-charge convention of nonpolarizable FFs, which may average out the influence of the membrane dielectric gradient. We show how polarity of small molecules influences their partitioning and describe key differences in the free energy surfaces between polarizable and nonpolarizable systems in these contexts. This work serves as a foundation for future investigations into polarizable simulations of drug partitioning, as well as simulations of membrane proteins.

Application of anionic-nonionic mixed micellar system for solubilization of methylene blue dye

Present study highlights the interaction of methylene blue (MB), a cationic dye, with anionic surfactant, sodium dodecyl sulfate (SDS), and its mixed micelles with a nonionic surfactant Triton X-114 (TX-114). The results obtained from UV–visible spectrophotometry were used to obtain the degree of solubilization in terms of binding constant (Kb) and partition coefficient (Kx) of dye in single and mixed micellar systems (MMS). Gibb’s free energies of partitioning and binding were also calculated for both systems. Specific conductance was measured to determine the CMC of single and mixed micellar media at five different temperatures, T = (293.15 – 333.15) K. Temperature-dependent thermodynamic parameters like Gibb’s free energy of micellization (ΔGomic), enthalpy of micellization (ΔHomic), and entropy of micellization (ΔSomic) were calculated using data of specific conductance measurements. Effect of concentration of TX-114 on Kx and Kb values of the MB in MMS is also investigated. Spectroscopic and conductometric results revealed that the anionic-nonionic mixed micellar system was better and more effective for the removal and solubilization of MB from aqueous system as compared to anionic micelles only. However, it has been observed that after a critical concentration an increase of non-ionic surfactant concentration has a reverse effect on solubilizing power of ionic-nonionic mixed micellar system. This indicates that the dye-surfactant interaction became weaker due to possible decrease in ionic character of mixed micelles when the high fraction of TX-114 was used.

Transferable and Polarizable Coarse Grained Model for Proteins─ProMPT.

The application of classical molecular dynamics (MD) simulations at atomic resolution (fine-grained level, FG), to most biomolecular processes, remains limited because of the associated computational complexity of representing all the atoms. This problem is magnified in the presence of protein-based biomolecular systems that have a very large conformational space, and MD simulations with fine-grained resolution have slow dynamics to explore this space. Current transferable coarse grained (CG) force fields in literature are either limited to only peptides with the environment encoded in an implicit form or cannot capture transitions into secondary/tertiary peptide structures from a primary sequence of amino acids. In this work, we present a transferable CG force field with an explicit representation of the environment for accurate simulations with proteins. The force field consists of a set of pseudoatoms representing different chemical groups that can be joined/associated together to create different biomolecular systems. This preserves the transferability of the force field to multiple environments and simulation conditions. We have added electronic polarization that can respond to environmental heterogeneity/fluctuations and couple it to protein's structural transitions. The nonbonded interactions are parametrized with physics-based features such as solvation and partitioning free energies determined by thermodynamic calculations and matched with experiments and/or atomistic simulations. The bonded potentials are inferred from corresponding distributions in nonredundant protein structure databases. We present validations of the CG model with simulations of well-studied aqueous protein systems with specific protein fold types─Trp-cage, Trpzip4, villin, WW-domain, and β-α-β. We also explore the applications of the force field to study aqueous aggregation of Aβ 16-22 peptides.

Crystallographic evidence of synthesized Ni(II) fluoride complex: Solubilization interaction of fluoride complex in anionic micellar media by conductometric and spectroscopic techniques

The X-ray crystallographic and physicochemical investigation of newly synthesized coordination complex of nickel (Trans-difluorobis(N,N-dimethylethane-1,2-diamine-k2N,N')nickel(II)octahydrate [Ni(dmen)2F2].8H2O is encompassed in this manuscript. The synthesized complex was characterized by elemental analysis, FTIR studies, magnetic measurements, electronic absorption measurements, and single-crystal X-ray diffraction analysis. The crystals are monoclinic in the P2(1)/c space group, with a = 8.0271(4) Å, b = 4.4509(8) Å, c = 15.1013(11)Å, α = 90°, β = 113.2340(10)°, γ = 90°. The crystal structure displays O-H⋯F and O-H⋯O hydrogen-bond interactions. Solubilization of [Ni(dmen)2F2].8H2O (NiDC) by anionic surfactant, sodium lauryl sulfate (SLS), in aqueous solutions in the pre-micellar, micellar and post-micellar concentration ranges was accomplished by UV–Visible spectroscopy and electrical conductivity measurements. The thermodynamic parameters of complex-surfactant interaction including standard entropy (ΔSmic), free energy (ΔGmic), and enthalpy (ΔHmic) of micelle formation were evaluated. The disruption of structured water in the near environment of hydrophobic groups of the surfactant was responsible for the increase in critical micelle concentration (CMC) with increasing temperature. The negative values of ΔGmic and ΔHmic indicate that solubilization of complex in micelles was spontaneous, in addition to enthalpy and entropy-driven. UV–Vis spectroscopy revealed the quantitative measure of interaction of the complex with surfactant in terms of partition constant (Kx), the free energy of partition (ΔGpart), binding coefficient (Kbind), and binding free energy (ΔGbind). The presence of surfactant led to a red-shift in UV–Vis spectra of NiDC which indicates their strong interaction. From the outcomes of the study, it is very clear that CMC in pure surfactants was lower than the CMC found with Ni-complex. The NMR study revealed that the complex is resided at the palisade layer by interacting with the functional moieties of hydrophobic chain. This indication well coincides with results of partitioning study by UV–Vis spectroscopy. The complex also has significant antioxidant and hemolytic activity against DPPH and RBCs respectively but it has no cyctotoxicity against 3 T3 cell lines.

Application of protic ammonium-based ionic liquids with carboxylate anions for phenol extraction from aqueous solution and their cytotoxicity on human cells

In this work, the removal of phenol from aqueous solution was investigated by screening three ionic liquids (ILs) having one common cation, trioctylammonium (TOA), combined with three different anions, namely 3,4-dimethylbenzoate (IL1), 4-tert-butylbenzoate (IL2), and 4-phenylbutanoate (IL3), at room temperature. The results indicate that [TOA][4-phenylbutanoate] (IL3) gave the best efficiency and, hence, was selected for the optimization of process parameters: pH, contact time, concentration, phase ratio, and temperature. The optimum conditions were found to be pH 5, contact time of 5 min, phase ratio (VIL/Vw) of 1:5, initial concentration of phenol of 3000 ppm, and temperature of 298 K. The extraction thermodynamics were studied, and the enthalpy, entropy, and free energy of partition were evaluated. The modes of interaction of these ILs with phenol were modeled using the Conductor-Like Screening Model for Real Solvent (COSMO-RS). Additionally, the cytotoxicity of these ILs toward human cells was investigated. The results indicate that they possess less toxicity than the more commonly used 1-butyl-1-methylpyrrolidinium bis-(trifluoromethylsulfonyl)imide. It has been concluded from the experimental results that ammonium-based ILs with carboxylate anions are efficient for extraction of phenol from polluted water.

Effect of nonionic surfactant on micellization thermodynamics and spectroscopic profile of dye-surfactant aggregation

Interactional study of triphenylmethane-based cationic dye i.e., basic violet-4 dye (BV) in the mixed-micellar system of two anionic surfactants viz. sodium dodecyl sulfate (NaDS) and sodium stearate (NaS) is encompassed in this manuscript. The composite micelles of nonionic surfactant triton X-100 (TX) served as better colloidal carriers to facilitate aggregation, deep penetration, and stability of dye molecules than single surfactants. The thermodynamics of the micellization was assessed conductometrically, whereas the extent of dye-surfactant interaction was quantified spectroscopically. The nonionic/anionic mixture favored micellization and lowered critical micellar concentration (CMC). Furthermore, it is observed that dye partitioning, binding, and micellization were spontaneous processes. The thermodynamic parameters including entropy, enthalpy, and Gibb’s free energy of micellization along with the determination of the CMC, degree of ionization are also explained. The parameters in terms of partition constant, partition coefficient, binding constant, Gibb’s free energy of partition, and binding were calculated from differential absorption spectroscopy. The comparative study revealed that NaDS/TX showed superior performance in dye penetration as compared to NaS/TX system.

Quantifying Membrane Curvature Sensing of Peripheral Proteins by Simulated Buckling and Umbrella Sampling

Membrane curvature plays an essential role in the organization and trafficking of membrane associated proteins. Comparison or prediction of the experimentally resolved protein concentrations adopted at different membrane curvatures requires direct quantification of the relative partitioning free energy. Here, we present a highly efficient and simple to implement a free-energy calculation method which is able to directly resolve the relative partitioning free energy of proteins as a direct function of membrane curvature, i.e., a curvature sensing profile, within (coarse-grained) molecular dynamics simulations. We demonstrate its utility by resolving these profiles for two known curvature sensing peptides, namely ALPS and α-synuclein, for a membrane curvature ranging from -1/6.5 to +1/6.5 nm-1. We illustrate that the difference in relative partitioning (binding) free energy between these two extrema is only about 13 kBT for both peptides, illustrating that the driving force of curvature sensing is subtle. Furthermore, we illustrate that ALPS and α-synuclein sense curvature via a contrasting mechanism, which is differentially affected by membrane composition. In addition, we demonstrate that the intrinsic spontaneous curvature of both of these peptides lies beyond the range of membrane curvature accessible in micropipette aspiration experiments, being about 1/7 nm -1. Our approach offers an efficient and simple to implement in silico tool for exploring and screening the membrane curvature sensing mechanisms of proteins.

Interactional study of a polymeric organotin complex in micellar media

In this manuscript, a study on interactions of a polymeric derivative of Tributyltin(IV) with [(2-Methylpropanoyl)amino]propanoic acid (TMP) in micellar media is presented. The study was conducted using two surfactants viz. Sodium 2-ethylhexylsulphate (SES) and Cetyltrimethylammonium bromide (CTAB). The solubilization parameters in terms of partition constant (K c ), partition coefficient (K x ), binding constant (K b ), Gibb’s free energy of partition (ΔG p ), and binding (ΔG b ) were investigated by UV–Visible spectrophotometer. The estimation of micellization thermodynamics including entropy (ΔS m ), enthalpy (ΔH m ), and Gibb’s free energy (ΔG m ) were determined conductometrically. The compound showed more interaction with the cationic surfactant as compared to anionic participating surfactant due to comparative electrostatic interactions. The partition coefficient (K x ) in the micellar media of CTAB was significantly higher (4.22 × 107) than SES media (1.33 × 105). The Gibb’s free energies of partition. Binding and micellization were higher in CTAB as compared to SES.

Thermodynamic and solubilization properties of a polynuclear copper complex in ionic surfactants media

The solubilization behavior of hexanuclear copper complex, [Cu6(η1 :μ2 -C4H10NO)4(η1 :η1 :μ2 -C5H9O2)4(η1 :μ1 -C5H9O2)2(μ 3-OH)2] (1) (where, C4H10NO = N,N-dimethylethanolamine and C5H9O2 = pivalic acid) ionic micellar media has been explored in this study. The interaction of copper cluster under investigation (1) was experimented with an anionic surfactant (sodium lauryl sulfate; SLS) and a cationic surfactant (cetyltrimethyl ammonium bromide; CTAB). Solubilization was observed in aqueous solutions of ionic surfactants at their pre-micellar, micellar and post-micellar concentrations ranges using UV–Visible spectroscopy and electrical conductivity. The thermodynamic attributes of micellization including standard entropy (ΔSmic ), enthalpy (ΔHmic ) and free energy (ΔGmic ) were estimated from electrical conductivity measurements. The negative values of ΔGmic and ΔHmic indicated the stability of micellization, in addition to the enthalpy and entropy-driven nature of the process. Thermodynamic studies demonstrate increases in the CMC of both surfactants due to incorporation of the copper complex in the micelles. Partitioning and binding parameters were revealed by UV–Vis spectroscopy to quantitatively measure the interaction of the copper cluster with the surfactant in terms of partition constant (Kc ), partition coefficient (Kx ), binding coefficient (Kbind ), and free energies of free energy of partition (ΔGpart ) and binding (ΔGbind ). The presence of cationic CTAB led to greater red-shift in UV–Vis study of 1 as compared to SLS due to stronger ionic interactions. The strong interaction and high solubility have been seen in 1 with CTAB as compared to SLS.

Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators.

Quorum sensing (QS) is a bacterial communication process mediated by both native and non-native small-molecule quorum sensing modulators (QSMs), many of which have been synthesized to disrupt QS pathways. While structure-activity relationships have been developed to relate QSM structure to the activation or inhibition of QS receptors, less is known about the transport mechanisms that enable QSMs to cross the lipid membrane and access intracellular receptors. In this study, we used atomistic MD simulations and an implicit solvent model, called COSMOmic, to analyze the partitioning and translocation of QSMs across lipid bilayers. We performed umbrella sampling at atomistic resolution to calculate partitioning and translocation free energies for a set of naturally occurring QSMs, then used COSMOmic to screen the water-membrane partition and translocation free energies for 50 native and non-native QSMs that target LasR, one of the LuxR family of quorum-sensing receptors. This screening procedure revealed the influence of systematic changes to head and tail group structures on membrane partitioning and translocation free energies at a significantly reduced computational cost compared to atomistic MD simulations. Comparisons with previously determined QSM activities suggest that QSMs that are least likely to partition into the bilayer are also less active. This work thus demonstrates the ability of the computational protocol to interrogate QSM-bilayer interactions which may help guide the design of new QSMs with engineered membrane interactions.

Expanding MPEx Hydropathy Analysis to Account for Electrostatic Contributions to Protein Interactions with Anionic Membranes.

Hydropathy plots are a crucial tool to guide experimental design, as they generate predictions of protein-membrane interactions and their bilayer topology. The predictions are based on experimentally determined hydrophobicity scales, which provide an estimate for the propensity and stability of these interactions. A significant improvement to the accuracy of hydropathy analyses was provided by the development of the popular Wimley-White interfacial and octanol hydrophobicity scales. These scales have been previously incorporated into the freely available MPEx (Membrane Protein Explorer) online application. Here, we introduce a substantial update to MPEx that allows for the consideration of electrostatic contributions to the bilayer partitioning free energy. This component originates from the Coulombic attraction or repulsion of charges between proteins and membranes. Its inclusion in hydropathy calculations increases the accuracy of hydropathy plot predictions and extends their use to more complex systems (i.e., anionic membranes). We illustrate the application of this analysis to studies on the membrane selectivity of antimicrobial peptides, the membrane partitioning of ion-channel gating modifiers, and the amyloid proteins α-synuclein and Tau, as well as pH-dependent bilayer interactions of diphtheria toxin and apoptotic inhibitor Bcl-xL.

Coarse-Grained Molecular Model for the Glycosylphosphatidylinositol Anchor with and without Protein.

Glycosylphosphatidylinositol (GPI) anchors are a unique class of complex glycolipids that anchor a great variety of proteins to the extracellular leaflet of plasma membranes of eukaryotic cells. These anchors can exist either with or without an attached protein called GPI-anchored protein (GPI-AP) both in vitro and in vivo. Although GPIs are known to participate in a broad range of cellular functions, it is to a large extent unknown how these are related to GPI structure and composition. Their conformational flexibility and microheterogeneity make it difficult to study them experimentally. Simplified atomistic models are amenable to all-atom computer simulations in small lipid bilayer patches but not suitable for studying their partitioning and trafficking in complex and heterogeneous membranes. Here, we present a coarse-grained model of the GPI anchor constructed with a modified version of the MARTINI force field that is suited for modeling carbohydrates, proteins, and lipids in an aqueous environment using MARTINI’s polarizable water. The nonbonded interactions for sugars were reparametrized by calculating their partitioning free energies between polar and apolar phases. In addition, sugar–sugar interactions were optimized by adjusting the second virial coefficients of osmotic pressures for solutions of glucose, sucrose, and trehalose to match with experimental data. With respect to the conformational dynamics of GPI-anchored green fluorescent protein, the accessible time scales are now at least an order of magnitude larger than for the all-atom system. This is particularly important for fine-tuning the mutual interactions of lipids, carbohydrates, and amino acids when comparing to experimental results. We discuss the prospective use of the coarse-grained GPI model for studying protein-sorting and trafficking in membrane models.

Spontaneous Curvature, Differential Stress, and Bending Modulus of Asymmetric Lipid Membranes

Lipid bilayers can exhibit asymmetric states, in which the physical characteristics of one leaflet differ from those of the other. This most visibly manifests in a different lipid composition, but it can also involve opposing lateral stresses in each leaflet that combine to an overall vanishing membrane tension. Here, we use theoretical modeling and coarse-grained simulation to explore the interplay between a compositional asymmetry and a nonvanishing differential stress. Minimizing the total elastic energy leads to a preferred spontaneous curvature that balances torques due to both bending moments and differential stress, with sometimes unexpected consequences. For instance, asymmetric flat bilayers, whose specific areas in each leaflet are matched to those of corresponding tensionless symmetric flat membranes, still exhibit a residual differential stress because the conditions of vanishing area strain and vanishing bending moment differ. We also measure the curvature rigidity of asymmetric bilayers and find that a sufficiently strong differential stress, but not compositional asymmetry alone, can increase the bending modulus. The likely cause is a stiffening of the compressed leaflet, which appears to be related to its gel transition but not identical with it. We finally show that the impact of cholesterol on differential stress depends on the relative strength of elastic and thermodynamic driving forces: if cholesterol solvates equally well in both leaflets, it will redistribute to cancel both leaflet tensions almost completely, but if its partitioning free energy prefers one leaflet over the other, the resulting distribution bias may even create differential stress. Because cells keep most of their lipid bilayers in an asymmetric nonequilibrium steady state, our findings suggest that biomembranes are elastically more complex than previously thought: besides a spontaneous curvature, they might also exhibit significant differential stress, which could strongly affect their curvature energetics.

Resolution limit of data-driven coarse-grained models spanning chemical space.

Increasing the efficiency of materials design remains a significant challenge given the large size of chemical compound space (CCS). The use of a chemically transferable coarse-grained model enables different molecular fragments to map to the same bead type, significantly increasing screening efficiency. Here, we propose new criteria for the design of coarse-grained models allowing for the optimization of their chemical transferability and evaluate the Martini model within this framework. We further investigate the scope of this transferability by parameterizing three Martini-like models in which the number of bead types ranges from 5 to 16. These force fields are fully compatible with existing Martini environments because they are parameterized by interpolating the Martini interaction matrix. We then implement a Bayesian approach to determining which chemical groups are likely to be present on fragments corresponding to specific bead types for each model. We demonstrate that a level of accuracy comparable to Martini is obtained with a force field with fewer bead types, using the water/octanol partitioning free energy (ΔGW→Ol) as our metric for comparison. However, the advantage of including more bead types is a reduction of uncertainty when back-mapping these bead types to specific chemistries. Just as reducing the size of the coarse-grained particles leads to a finer mapping of conformational space, increasing the number of bead types yields a finer mapping of CCS. Finally, we note that, due to the large size of fragments mapping to a single Martini bead, a resolution limit arises when using ΔGW→Ol as the only descriptor when coarse-graining CCS.

Thermodynamic and solution properties of sodium valporate in aqueous solution and its interaction with cetyl trimethylammonium bromide (CTAB)

This manuscript reports the volumetric, viscometric and aggregation properties of sodium valporate in aqueous solution. The interaction of drug with cationic surfactant (CTAB) was also studied. From volumetric study, partial molar volume, Hepler's constant, partial molar expansivity and isobaric thermal expansion coefficient were calculated while from viscometric study, the constants of Jones-Dole equation and thermodynamic parameters of viscous flow like free energy change, entropy change and enthalpy change were calculated. Critical micelle concentration of drug at four different temperatures was measured by surface tension and electrical conductivity measurements. The data was used to calculate surface excess concentration and thermodynamic parameters for the micellization process i.e. free energy of adsorption, free energy, entropy and enthalpy of micellization. Spectroscopic study of the drug/surfactant interaction was helpful to calculate partition coefficient, free energy of partition, binding constant and free energy of binding.

Investigating Drug-Membrane Permeability across Chemical Compound Space using High-Throughput Coarse-Grained Simulations

In an in silico search for structure-property relationships, the extensive computational resources required by atomistic molecular dynamics simulations renders a thorough exploration of chemical compound space unfeasible. This issue can be efficiently addressed by relying on coarse-grained models, which provide a means to mitigate the computational expense while still capturing the relevant physical properties of the system under investigation. In this work, we introduce a high-throughput screening of chemical compound space by means of coarse-grained molecular dynamics simulations of the Martini force field, and apply it to the determination of the insertion thermodynamics of an ensemble of small molecules in a phospholipid bilayer environment. We employ a novel importance sampling technique in coarse-grained compound space, akin to the more traditional sampling of conformational space used in computational physics. The study allows us to define a smooth permeability surface as a function of two molecular properties: pKa in water and a bulk organic/aqueous partitioning free energy. Moreover, we show that Martini, as a chemically transferable coarse-grained model, yields a significant reduction in the size of chemical space. This makes our findings representative of the behavior of a set of more than 500,000 chemically different small molecules in a lipid bilayer system, resulting in a more detailed understanding of the underlying structure-property relationships between drug chemistry and passive-permeation thermodynamics.

Drug-Membrane Permeability across Chemical Space.

Unraveling the relation between the chemical structure of small druglike compounds and their rate of passive permeation across lipid membranes is of fundamental importance for pharmaceutical applications. The elucidation of a comprehensive structure–permeability relationship expressed in terms of a few molecular descriptors is unfortunately hampered by the overwhelming number of possible compounds. In this work, we reduce a priori the size and diversity of chemical space to solve an analogous—but smoothed out—structure–property relationship problem. This is achieved by relying on a physics-based coarse-grained model that reduces the size of chemical space, enabling a comprehensive exploration of this space with greatly reduced computational cost. We perform high-throughput coarse-grained (HTCG) simulations to derive a permeability surface in terms of two simple molecular descriptors—bulk partitioning free energy and pKa. The surface is constructed by exhaustively simulating all coarse-grained compounds that are representative of small organic molecules (ranging from 30 to 160 Da) in a high-throughput scheme. We provide results for acidic, basic, and zwitterionic compounds. Connecting back to the atomic resolution, the HTCG predictions for more than 500 000 compounds allow us to establish a clear connection between specific chemical groups and the resulting permeability coefficient, enabling for the first time an inverse design procedure. Our results have profound implications for drug synthesis: the predominance of commonly employed chemical moieties narrows down the range of permeabilities.

A Practical View of the Martini Force Field.

Martini is a coarse-grained (CG) force field suitable for molecular dynamics (MD) simulations of (bio)molecular systems. It is based on mapping of two to four heavy atoms to one CG particle. The effective interactions between the CG particles are parametrized to reproduce partitioning free energies of small chemical compounds between polar and apolar phases. In this chapter, a summary of the key elements of this CG force field is presented, followed by an example of practical application: a lipoplex-membrane fusion experiment. Formulated as hands-on practice, this chapter contains guidelines to build CG models of important biological systems, such as asymmetric bilayers and double-stranded DNA. Finally, a series of notes containing useful information, limitations, and tips are described in the last section.

Insights into the Interactions of Sulfamethoxazole with Organized Assemblies of Ionic and Nonionic Surfactants.

This work reports the physicochemical behavior of antibiotic drug sulfamethoxazole (SMX) in the presence of different surfactants, viz., cetyl trimethyl ammonium bromide (CTAB), dodecyl trimethyl ammonium bromide, didodecyl dimethyl ammonium bromide, sodium dodecyl sulfate, sodium deoxycholate, Tween 80, and Tween 20. The drug-surfactant systems were studied by UV-visible and fluorescence spectroscopies to assess the binding constants ( Kb), partition coefficient ( Kx), free energy of partition (Δ Gp), aggregation number ( Nagg), and quenching constant ( KSV). Solubilization studies were carried out to understand the encapsulation efficiency of the system, which was found to increase as a function of CTAB concentration. Surface tension measurements enabled us to determine the change in critical micelle concentration as well as to calculate the variation in surface parameters of surfactant in the presence of drug, viz., surface pressure (π), surface excess concentration (γmax), and minimum area ( Amin). In addition, UV-visible, fluorescence, and circular dichroism studies were carried out to check the effects of surfactant-based SMX formulation on serum proteins.