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The very wide applications of LTA zeolites, e.g., tritiated water storage, imply that a precise atomic-scale description of the adsorption processes taking place in their structure is crucial.

Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.

Pristine graphene, a range of graphene oxides, and silica substrates were used to investigate the effect of surface hydrophilicity on supported lipid bilayers by means of all-atom molecular dynamics simulations. Supported 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers were found in close-contact conformations with hydrophilic substrates with as low as 5% oxidation level, while self-assembled monolayers occur on pure hydrophobic graphene only. Lipids and water at the surface undergo large redistribution to maintain the stability of the supported bilayers. Deposition of bicelles on increasingly hydrophilic substrates shows the continuous process of reshaping of the supported system and makes intermediate stages between self-assembled monolayers and supported bilayers. The bilayer thickness changes with hydrophilicity in a complex manner, while the number of water molecules per lipid in the hydration layer increases together with hydrophilicity.

The very wide range of applications of LTA zeolites, including the storage of tritiated water, implies that a detailed and accurate atomic-scale description of the adsorption processes taking place in their structure is crucial. To unravel with an unprecedented accuracy the mechanisms behind the water filling in NaA, we have conducted a systematic ab initio molecular dynamics investigation. Two LTA structural models, the conventional Z4A and the reduced one ZK4, have been used for static and dynamic ab initio calculations, respectively. After assessing this reduced model with comparative static DFT calculations, we start the filling of the α and β cages by water, molecule by molecule. This allowed us to thoroughly study the interaction of water molecules with the zeolite structure and between water molecules, progressively forming H-bond chains and ring patterns as the cage is being filled. The adsorption energies could then be calculated with an unprecedented accuracy, which showed that the interaction of the molecules with the zeolite weakens as their number increases. By these methods, we have been able to highlight the primary role of Na+ cations in the interaction of water with zeolite, and inversely, the role of water in the displacement of cations when it is sufficiently solvated, allowing the passage between the α and β cages. This phenomenon is possible thanks to the inhomogeneous distribution of water molecules on the cationic sites, as shown by our AIMD simulations, which allows the formation of water clusters. These results are important because they help in understanding how the coverage of cationic sites by water will affect the adsorption of other molecules inside the Na-LTA zeolite.

The composition of the plasma membrane of malignant cells is thought to influence the cellular uptake of cisplatin and to take part in developing resistance to this widespread anti-cancer drug. In this work we study the permeation of cisplatin through the model membranes of normal and cancer cells using molecular dynamics simulations. A special attention is paid to lipid asymmetry and cholesterol content of the membranes. The loss of lipid asymmetry, which is common for cancer cells, leads to a decrease in their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change in the cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5–6 orders of magnitude higher than one of the membranes with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

Molecular modeling in pharmacology is a promising emerging tool for exploring drug interactions with cellular components. Recent advances in molecular simulations, big data analysis, and artificial intelligence (AI) have opened new opportunities for rationalizing drug interactions with their pharmacological targets. Despite the obvious utility and increasing impact of computational approaches, their development is not progressing at the same speed in different fields of pharmacology. Here, we review current in silico techniques used in cardiovascular diseases (CVDs), cardiological drug discovery, and assessment of cardiotoxicity. In silico techniques are paving the way to a new era in cardiovascular medicine, but their use somewhat lags behind that in other fields.

This work is motivated by the results obtained during a study on the tritiated water adsorbed in zeolite [L. Frances et al., J. Phys. Chem. C, 119, 28462 (2015)]. The decomposition of water by radiolysis leads to the production of dioxygen and dihydrogen as main stable products. By studying the evolution of their quantities of matter, one can note an increase in a first stage, followed by a decrease after a few hundred days of storage until complete disappearance. This interesting process depends on the water loading ratios, expressed in mass percentage, lying between 4%, and 19%; such a phenomenon is not observed in saturated zeolite. Our goal is to determine, through numerical simulations, how this disappearance, which is associated with the recombination of the radiolysis products, occurs by making a microscopic study on the adsorption of H2O, H2, and O2 molecules on 4A zeolite (Z4A). Computational physics is useful to understand the effects of molecule adsorption on its structure and also to closely examine the molecule-zeolite and molecule-molecule interactions. Indeed, different simulation methods are used from static to dynamic studies employing both quantum and classical tools with the periodical structure of Z4A. To summarize, the adsorption of molecules from the radiolysis of water are studied according to different points of view (quantum and classical) using various numerical simulation tools, such as density functional theory for ab initio structural optimization and energy calculation, Monte Carlo to study the distribution of the adsorbed molecules in the zeolite, and molecular dynamics to follow the evolution of the system (molecule + zeolite) over time depending on the temperature, in order to extract as much information as possible (structurally, statistically, energy, electronically) to understand the main problematic of this work: How do stable molecules issued from radiolysis recombine in Z4A?

free open access article 31 p.; International audience; In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupling of the drugs to lipoproteins and stability was assessed by mass and raman spectrometry analysis. Cisplatin vectorized in LDLs led to better tumor growth suppression with strongly reduced adverse effects such as a renal or liver toxicity. AC1LINNC vectorized into HDLs induced a strong oxidative burst in macrophages and innate anti-cancer immune response. Cumulative anti-tumor effect was observed for both drug-loaded lipoproteins. Altogether, our data show that lipoproteins from patient’s blood can be used as natural nanocarriers allowing cell specific targeting, paving the way toward more efficient, safer and personalized use of chemo-and immunotherapeutic drugs in cancer

International audience; Arginase is involved in a wide range of pathologies including cardiovascular diseases and infectious diseases whilst it is also a promising target to improve cancer immunotherapy. To date, only a limited number of inhibitors of arginase have been reported. Natural polyphenols, among them piceatannol, are moderate inhibitors of arginase. Herein, we report our efforts to investigate catechol binding by quantum chemistry and generate analogues of piceatannol. In this work, we synthesized a novel series of amino-polyphenols which were then evaluated as arginase inhibitors. Their structure–activity relationships were elucidated by deep quantum chemistry modelling. 4-((3,4-Dihydroxybenzyl)amino)benzene-1,2-diol 3t displays a mixed inhibition activity on bovine and human arginase I with IC50 (Ki) values of 76 (82) μM and 89 μM, respectively.

The development of elongated nanoparticles for drug delivery is of growing interest in recent years, due to longer blood circulation and improved efficacy compared to spherical counterparts. Squalenoyl-doxorubicin (SQ-Dox) conjugate was previously shown to form elongated nanoparticles with improved therapeutic efficacy and decreased toxicity compared to free doxorubicin. By using experimental and computational techniques, we demonstrate here that the specific physical properties of SQ-Dox, which include stacking and electrostatic interactions of doxorubicin as well as hydrophobic interactions of squalene, are involved in the formation of nanoassemblies with diverse elongated structures. We show that SQ-Dox bioconjugate concentration, ionic strength, and anion nature can be used to modulate the shape and stiffness of SQ-Dox nanoparticles. As those parameters are involved in nanoparticle behavior in biological media, these findings could bring interesting opportunities for drug delivery and serve as an example for the design of original nanodrugs with stacking properties tuned for particular clinical purposes.

International audience; In the field of nanomedicine, nanostructured nanoparticles (NPs) made of self-assembling prodrugs emerged in the recent years with promising properties. In particular, squalene-based drug nanoparticles have already shown their efficiency through in vivo experiments. However, a complete pattern of their stability and interactions in the blood stream is still lacking. In this work we assess the behavior of squalene-adenosine (SQAd) nanoparticles-whose neuroprotective effect has already been demonstrated in murine models-in the presence of fetal bovine serum (FBS) and of bovine serum albumin (BSA), the main protein of blood plasma. Extensive physicochemical characterizations were performed using Small Angle Neutron Scattering (SANS), cryogenic transmission electron microscopy (Cryo-TEM), circular dichroism (CD), steady-state fluorescence spectroscopy (SSFS) and isothermal titration calorimetry (ITC) and in silico by means of ensemble docking simulations with human serum albumin (HSA). Significant changes in the colloidal stability of the nanoparticles in the presence of serum albumin were observed. SANS, CD and SSFS analyses demonstrated an interaction 2 between SQAd and BSA, with a partial disassembly of the nanoparticles in the presence of BSA and the formation of a complex between SQAd and BSA. The interaction free energy of SQAd nanoparticles with BSA derived from ITC experiments, is about-8 kcal/mol which is further supported in silico by ensemble docking simulations. Overall, our results show that serum albumin partially disassembles SQAd nanoparticles by extracting individual SQAd monomers from them. As a consequence, the SQAd nanoparticles would act as a circulating reservoir in the blood stream. The approach developed in this study could be extended to other soft organic nanoparticles.

Interaction of platinum-based drugs with proteins containing sulphur amino acids is usually argued as one of the major reasons for the observed resistance to these drugs, mainly due to the deactivation of the native compounds by very efficient thiolation processes in the organism. In this work, we have investigated the detailed thermodynamics and kinetics of reaction between cisplatin cis-[PtCl2(NH3)2] and its major hydrolysed forms (monohydroxocisplatin cis-[PtCl(OH)(NH3)2] and monoaquacisplatin cis-[PtCl(H2O)(NH3)2]+) with various thiolates (methanethiolate, cysteine and glutathione) and methionine. We have used a demanding quantum chemistry approach at the MP2 and DFT levels of theory to determine the Gibbs free energies and the barrier of reactions of the most possible reaction paths. The substitution of the four ligands of the complexes studied here (Cl−, OH−, H2O and NH3) can either proceed by direct thiolations or bidentations. Our Raman spectroscopy measurements show that only two thiolations actually occur, although four are possible in principle. The reason could lie in the bidentation reactions eventually taking place after each thiolation, which is backed up by our computational results. The observed lability scale of the ligands under thiolate exposure was found to be in the following order H2O > Cl− ≈ NH3(trans) > NH3(cis) > OH−, the difference between ammine ligands being induced by a significant trans-labilization by thiolates. Finally, the S,N bidentation is shown to be preferred with respect to the S,O one.

In this work the permeability of a model asymmetric plasma membrane, for ions, water and the anti-cancer drugs cisplatin and gemcitabine is studied by means of all-atom molecular dynamics simulations. It is shown that permeability of the membranes increases from one to three orders of magnitude upon membrane bending depending on the compound and the sign of curvature. Our results show that the membrane curvature is an important factor which should be considered during evaluation of drug translocation.TOC GRAPHICS

Comptes Rendus Chimie - In Press.Proof corrected by the author Available online since jeudi 22 mars 2018

In this work, realistic models of membranes of normal and cancer cells are developed. A special focus is given to their cholesterol content. It is shown that the loss of lipid asymmetry in the membranes of cancer cells leads to a decrease of their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change of cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5-6 orders of magnitude higher than one of the membrane with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

We have studied the interaction of three clinically promising squalenoylated drugs (gemcitabine-squalene, adenine-squalene, and doxorubicin-squalene) with low-density lipoproteins (LDL) by means of atomistic molecular dynamics simulations. It is shown that all studied squalenoylated drugs accumulate inside the LDL particles. This effect is promoted by the squalene moiety, which acts as an anchor and drives the hydrophilic drugs into the hydrophobic core of the LDL lipid droplet. Our data suggest that LDL particles could be a universal carriers of squalenoylated drugs in the bloodstream. Interaction of gemcitabine-squalene with human serum albumin (HSA) was also studied by ensemble of docking simulations. It is shown that HSA could also act as a passive carrier of this bioconjugate. It should be noted that the binding of squalene moiety to HSA was unspecific and did not occur in the binding pockets devoted to fatty acids.

The conformational dynamics of human serum albumin (HSA) was investigated by principal component analysis (PCA) applied to three molecular dynamics trajectories of 200 ns each. The overlap of the essential subspaces spanned by the first 10 principal components (PC) of different trajectories was about 0.3 showing that the PCA based on a trajectory length of 200 ns is not completely convergent for this protein. The contributions of the relative motion of subdomains and of the subdomains (internal) distortion to the first 10 PCs were found to be comparable. Based on the distribution of the first 3 PC, 10 protein conformers are identified showing relative root mean square deviations (RMSD) between 2.3 and 4.6 A. The main PCs are found to be delocalized over the whole protein structure indicating that the motions of different protein subdomains are coupled. This coupling is considered as being related to the allosteric effects observed upon ligand binding to HSA. On the other hand, the first PC of one of the three trajectories describes a conformational transition of the protein domain I that is close to that experimentally observed upon myristate binding. This is a theoretical support for the older hypothesis stating that changes of the protein onformation favorable to binding can precede the ligand complexation. A detailed all atoms PCA performed on the primary Sites 1 and 2 confirms the multiconformational character of the HSA binding sites as well as the significant coupling of their motions.

STAT3 protein, which is known to be involved in cancer development, is a promising target for anticancer therapy. Successful inhibitors of STAT3 should not affect an activity of closely related protein STAT1, which makes their development challenging. The mechanisms of selectivity of several existing STAT3 inhibitors are not clear. In this work, we studied molecular mechanisms of selectivity of 13 experimentally tested STAT3 inhibitors by means of extensive molecular dynamics and ensemble docking simulations. It is shown that all studied inhibitors bind to the large part of the protein surface in an unspecific statistical manner. The binding to the dimerization interface of the SH2 domain, which is usually considered as the main target region, is not energetically preferable. Binding in this region is remarkably similar for STAT1 and STAT3 proteins and cannot explain experimentally observed selectivity toward STAT3. We propose a new mechanism of selectivity called "selectivity by distraction" for existing STAT3 inhibitors. This mechanism is based on equilibrium statistical partitioning of inhibitor molecules between protein domains. The unspecific binding of inhibitors to the DNA-binding and the coil-coil domains is stronger in STAT1 in comparison to STAT3 while the energies of their binding to SH2 domains are comparable. This "distracts" inhibitor molecules from the SH2 domain of STAT1 and leads to higher effective concentration of inhibitors in the vicinity of the SH2 domain of STAT3.

We explore with Molecular Dynamics simulations and a statistical model, the ability of carbon nanotubes to be internalized into a model lipid bilayer as a function of their length. The hydrophobicity is one of the key factors responsible for the insertion process. The membrane asymmetry is also needed to drive a complete translocation. Our data demonstrates that shorter nanotubes have a stronger propensity to passively penetrate the bilayer and reach the cytoplasm. Carbon nanotubes excretion appears mostly impossible whatever their length.

International audience; Bioactive molecules, cationic peptides among them, are nowadays well-recognized in modern pharmacology for their drug potential. However, they usually suffer from poor translocation across cell membranes, and specific drug carriers should be designed to circumvent this problem. In the present study, the uptake mechanism of fullerene bearing cationic ammonium groups by membranes modeled as lipid bilayers is investigated using extensive molecular dynamics simulations and free-energy calculations. Three main results issued from this work can be drawn. First, the fullerene core appears to be a good drug vector since it greatly enhances the uptake of the cationic groups by the membrane. Second, we show that the amino derivatives should be deprotonated at the lipid headgroup level in order to fully translocate the membrane by passive diffusion. Finally, the fullerenes bearing too many cationic groups display mostly a hydrophilic character; thus, the lipophilic fullerene core is not anymore effective as an insertion enhancer. Therefore, the lipid bilayer appears to be very selective with respect to the amount of amino groups conjugated with C60.

International audience; Real surfaces display defects originating either from thermodynamic principles or from local instabilities. In order to help and characterize these surfaces and their defects, infrared spectroscopy of physisorbed test molecules can be used. As an example, we study the behavior of the infrared response of CO molecules randomly deposited on ionic surfaces of MgO and NaCl with the concentration of dipolar defects randomly distributed on these surfaces. The vibrational peak is shifted and asymmetrically broadened when the defect concentration increases as a result of surface inhomogeneity, in semi-quantitative agreement with experimental data.

International audience; Most studies of the interactions of neat and functionalized fullerenes with cells have focused so far on their ability to cross the cell membrane envelopes. Membranes are, however, also host to a large number of proteins responsible for various cellular functions. Among these, ion channels are prominent components of the nervous system. Recently, it was shown that fullerenes may act as blockers or modulators of a variety of K+ channels. Here we use computer simulations to investigate the propensity of such nanocompounds to bind to K+ channels. Our results based on extensive atomistic molecular dynamics simulations reveal a variety of specific binding sites depending on the structure and properties of the channel. The corresponding binding free energies and putative mechanisms suggest that C60 may indeed effectively hinder the function of K+ channels and hence induce toxicity.

Real surfaces display defects originating either from thermodynamic principles or from local instabilities. In order to help and characterize these surfaces and their defects, infrared spectroscopy of physisorbed test molecules can be used. As an example, we study the behavior of the infrared response of CO molecules randomly deposited on ionic surfaces of MgO and NaCl with the concentration of dipolar defects randomly distributed on these surfaces. The vibrational peak is shifted and asymmetrically broadened when the defect concentration increases as a result of surface inhomogeneity, in semi-quantitative agreement with experimental data.

Growing perfect monatomic chains on surfaces is generally a hard task since it depends strongly on the experimental conditions and on the species used as templates or adsorbates. In the present study, the growth of Co and Ag monatomic wires on a Pt(9 9 7) vicinal surface is investigated over a large range of temperature. A semi-empirical potential is used to extract the main diffusion barriers responsible for the growth of Co and Ag wires on the Pt(9 9 7) vicinal surface. Kinetic Monte Carlo simulations are performed to investigate the wire formation at step-edges. We show that step decoration occurs at 150 K for Ag and at temperatures higher than 250 K for Co in agreement with growth experiments. If no interdiffusion is taken into account, Co and Ag behave similarly and perfect wires form between 150 and 500 K for Ag and between 300 and 500 K for Co. In the case of Co, an exchange mechanism leading to interlayer diffusion at step-edges is shown to strongly influence the temperature range for which the perfect wires are observed. An activation barrier of 0.65 eV for this mechanism is found to be adequate to reproduce the experimental features observed by Gambardella et al. [P. Gambardella, M. Blanc, L. Burgi, K. Kuhnke, K. Kern, Surf. Sci., 449 (2000) 93]. At higher temperatures, above 500 K, detachment from steps strongly hinders the wire formation at step feet. As a main conclusion, the exchange diffusion barrier can be extracted directly from the comparison between observation of step decoration and numerical simulations.

Interaction of fullerenes with asymmetric and curved DOPC/DOPS bicelles is studied by means of coarse-grained molecular dynamics simulations. The effects caused by asymmetric lipid composition of the membrane leaflets and the curvature of the membrane are analyzed. It is shown that the aggregates of fullerenes prefer to penetrate into the membrane in the regions of the moderately positive mean curvature. Upon penetration into the hydrophobic core of the membrane fullerenes avoid the regions of the extreme positive or the negative curvature. Fullerenes increase the ordering of lipid tails, which are in direct contact with them, but do not influence other lipids significantly. Our data suggest that the effects of the membrane curvature should be taken into account in the studies concerning permeability of the membranes to fullerenes and fullerene-based drug delivery systems.

Transport of four metallic salts (CuCl 2 , ZnCl 2 , NiCl 2 and CaCl 2 ) through a polyamide nanofiltration (NF) membrane has been investigated experimentally from rejection rate and tangential streaming potential measurements. Rejection rates have been further analyzed by means of the steric, electric and dielectric exclusion (SEDE) homogeneous model with the effective dielectric constant of the solution inside pores as the single adjustable parameter. The volume charge density inside pores has been assessed from tangential streaming potential experiments by considering the effective dielectric constant inside pores instead of the bulk one. The conventional NF theory (i.e. disregarding dielectric effects) has been found to be unable to describe the experimental sequence of rejection rates (CuCl 2 > ZnCl 2 ≈ NiCl 2 > CaCl 2 ). It has been shown that the rejection rate sequence can be explained by the combination of the dielectric exclusion via image charges and the Donnan effect in the case of asymmetric salts with divalent counter-ions. The influence of the characteristic size of ions on the magnitude of the Born effect may explain the almost identical rejection rates measured with ZnCl 2 and NiCl 2 whereas a significant variation of the membrane volume charge density has been put in evidence by electrokinetic measurements carried out in both media.

Study of the mechanisms understanding how chemically functionalized carbon nanotubes internalize into mammalian cells is important in view of their design as new tools for therapeutic and diagnostic applications. The initial contact between the nanotube and the cell membrane allows elucidation of the types of interaction that are occurring and the contribution from the types of functional groups at the nanotube surface. Here we offer a combination of experimental and theoretical evidence of the initial phases of interaction between functionalized carbon nanotubes with model and cellular membranes. Both experimental and theoretical data reveal the critical parameters to determine direct translocation of the nanotubes through the membrane into the cytoplasm as a result of three distinct processes that can be summarized as landing, piercing and uptake. journal article research support, non-u.s. gov't 2013 Nov 07 2013 09 05 imported

International audience; Parameterization of molecular complexes containing a metallic compound, such as cisplatin, is challenging due to the unconventional coordination nature of the bonds which involve platinum atoms. In this work, we develop a new methodology of parameterization for such compounds based onquantum dynamics (QD) calculations. We show that the coordination bonds and angles are more flexible than in normal covalent compounds. The influence of explicit solvent is also shown to be crucial to determine the flexibility of cisplatin in quantum dynamics simulations. Two empirical topologies of cisplatin were produced by fitting its atomic fluctuations against QD in vacuum and QD with explicit first solvation shell of water molecules respectively. A third topology built in a standard way from the static optimized structure was used for comparison. The later one leads to an excessively rigid molecule and exhibits much smaller fluctuations of the bonds and angles than QD reveals. It is shown that accounting for thehigh flexibility of cisplatin molecule is needed for adequate description of its first hydration shell. MD simulations with flexible QD-based topology also reveal a significant decrease of the barrier of passive diffusion of cisplatin accross the model lipid bilayer. These results confirm that flexibility of organ-ometallic compounds is an important feature to be considered in classical molecular dynamics topologies. Proposed methodology based on QD simulations provides a systematic way of building such topologies.

The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.

International audience; The unfolding of the reduced human serum albumin (HSA) was simulated by generating four molecular dynamics (MD) trajectories of 160 ns each at 350, 375, 400, and 425 K, respectively. A principal components analysis (PCA) was performed on the four trajectories. Based on this analysis, 17 representative protein conformers were identified and subsequently used to construct a sequence of partially unfolded structures. They were ordered according to their decreasing α-helix fractions. The structural evolution in this unfolding sequence was found to be continuous at global but also at local level supporting the hypothesis that the protein unfolding pathway is not significantly dependent on the simulation temperature. As a result, the α-helix fraction of the protein appears to be a good reaction coordinate for the unfolding process, as it was previously suggested by experiments. Based on this observation, two conformers in the unfolding sequence were predicted to be close to the equilibrium structure of reduced HSA thus providing a first theoretical model for this protein form.

Ab initio calculations are used to calculate the atomic charges in the selectivity filter part of KcsA potassium channel according to the Merz–Kollman–Singh scheme. On the basis of a long molecular dynamics simulation, we show that these charges deviate significantly from the values usually implemented in the most common force fields. These consequent changes may considerably influence our views on the mechanistics of the potassium diffusion process and give strong evidence that the application of electronically polarizable force fields is necessary.

The lipid dioctadecylamine (DODA) has been shown to self-organize in plate-like structures in aqueous solution. While in a previous model, we investigated by simulations its mesoscopic collective behaviour, here, we considered atomic partial charge distribution as determined by ab initio quantum chemical computations, and its relationship with different conformations of the DODA molecule. After comparison of the charges obtained at different levels of theory on the stretched form of DODA, we show that gas phase charges are sufficient to represent what appears to be an intrinsic property of the lipid, independently from the solvent. As the molecule becomes distorted, significant partial charge fluctuations appear along the aliphatic chains.

The influence of a static scanning tunneling microscope (STM) tip on the diffusion of xenon atoms adsorbed on a Cu(1 1 0) stepped surface is studied. Semi-empirical potentials for the Xe–surface interaction and a N-body energy based method for the Xe–tip contribution are used to calculate the adsorption energy of adsorbates in the STM junction. First, we analyse the variation of this energy when the adatom is placed near a step edge and for different tip positions. When the tip is situated in the neighbourhood of the step edge, the Ehrlich–Schwoebel barrier experienced by the adatom is lowered. This opens a specific diffusion channel, allowing a possible crossing of the step edge. Second, through a kinetic Monte Carlo approach coupled to the elastic scattering quantum chemistry method, the noisy tunneling current created by the random motion of diffusing atoms in the vicinity of the tip can be analyzed. We show that, by counting the number of diffusion events, we can determine effective barriers related to the most dominant processes contributing to the diffusion at a particular temperature. We also demonstrate that the interaction mode of the tip (attractive or imaging) greatly modifies the diffusion processes.

Heat shock protein 33 (Hsp33) is activated in the presence of H2O2 by a very interesting redox switch based on a tetra-coordinated zinc–cysteine complex present in the fully reduced and inactive protein form. The oxidation of this zinc center by H2O2 induces formation of two S–S bridges and the zinc release followed by the protein unfolding. We report here a theoretical study of the step-by-step sequence of the overall process starting with the oxidation of the first cysteine residue and ending with the zinc release. Each reaction step is characterized by its Gibbs free energy barrier (∆G ‡). It is predicted that the first reaction step consists in the oxidation of Cys263 by H2O2 which is by far the most reactive cysteine (∆G ‡ = 15.4 kcal mol−1). The next two reaction steps are the formation of the first S–S bridge between Cys263 and Cys266 (∆G ‡ = 13.6 kcal mol−1) and the oxidation of Cys231 by H2O2 (∆G ‡ = 20.4 kcal mol−1). It is then shown that the formation of the second S–S bridge (Cys231–Cys233) before the zinc release is most unlikely (∆G ‡ = 34.8 kcal mol−1). Instead, the release of zinc just after the oxidation of the third cysteine (Cys231) is shown to be thermodynamically (dissociation Gibbs free energy ∆G d = 6.0 kcal mol−1) and kinetically (reaction rate constant k d ≈ 106 s−1) favored. This result is in good agreement with the experimental data on the oxidation mechanism of Hsp33 zinc center available to date.

Catestatin, a cationic and hydrophobic 21-amino acid fragment of chromogranin A, is known to be a non-competitive nicotinic antagonist acting through nicotinic acetylcholine receptors (nAChRs) to inhibit catecholamine release. Since this receptor is the target of several neuronal and non-neuronal disorder prophylaxes and treatments, this study aims at the elucidation of the binding of human catestatin to the entire nAChR reconstructed in lipid bilayers by means of docking followed by full atomistic molecular dynamics simulations. The obtained results show that the minimum free energy for the binding of the peptide and the receptor attains minimal values for locations at the pore site and in the outer beta subunit. This result is consistent with previous studies showing that catestatin occludes the pore opening. A new finding is an additional even stronger binding seat at the beta subunit and that membrane presence could be an important factor. Specific amino acids involved in catestatin binding have been identified, indicating targets for point mutation studies. In addition to improving the understanding of the interaction between the peptide and muscle-type and even other nAChR subtypes, the results of this study provide directions for future peptidomimetic research.

International audience; The curvature of biological membranes is known to be an important influence on important phenomena such as membrane fusion, endocytosis, and the functioning of integral membrane proteins. There is a growing demand for analytical tools that are able accommodate molecular dynamics trajectories of significantly curved lipid bilayers. In this work, an algorithm for determining the shape and curvature of a nonplanar lipid bilayer in molecular dynamics simulations is proposed. The algorithm calculates the coordinates of the midline and the curvature of the bilayer as well as the local normal to it at any point on the membrane, which is bent arbitrarily in a single plane and is topologically equivalent to an infinite bilayer. The algorithm is implemented as a C++ program and tested by exploring the molecular dynamic trajectories of a highly curved meander-like asymmetric lipid bilayer. The algorithm is general enough to allow it to be easily applied to other geometries of nonplanar membrane systems.

We present a theoretical study of the sum frequency generation (SFG) for the ammonia molecule adsorbed on the MgO(100) surface. This particular system could be a model for experimentalists in order to test this nonlinear technique, mainly for two reasons. First, the ammonia molecules can be considered in a first approximation as isolated on the surface due to repulsive lateral interactions. Second, the symmetry of ammonia and its particular equilibrium configuration on this surface allow us to separate the SFG response in a part which depends only on the non linear susceptibility of the molecules and an other part that characterizes the experimental setup. As a consequence, the bandshifts and widths of the SFG and infrared (IR) signals can be directly compared. Within the accuracy of the vibrational dependence of the molecular parameters, our calculations predict that the SFG signals connected to the symmetric vibrational modes should be more intense than the antisymmetric ones, in consistency with the IR...

Although molecular dynamics simulations of highly curved lipid bilayers have become increasingly popular in recent years, there is no simple and general method of computing the shape and curvature of the bilayer, which is bent arbitrarily in three dimensions. In this work we propose a method, which allows computing local normal, mean and Gaussian curvatures at any point of an arbitrarily curved lipid membrane using molecular dynamics trajectories. The method is based on the analysis of local membrane patches and is applicable to the membranes of any shape and topology – bilayers, vesicles, micelles, bicelles, etc. The method is applied to a highly curved asymmetric DOPC/DOPS lipid bilayer simulated by means of extended coarse-grained molecular dynamics simulations. It is shown that addition of cholesterol makes the membrane more topologically heterogeneous by increasing the content of highly curved regions with either saddle-like or sphere-like topology. The topology of the DOPS lipid domains is more sensitive to the addition of cholesterol than DOPC domains.

Potential energy calculations are performed in order to interpret the high-order commensurate (13×18) and (2×18) structures of the CF4 layer adsorbed on Cu(110) determined from helium diffraction experiments. We find that the most stable geometry at 0 K is a low order commensurate (2×2) phase containing two CF4 molecules which are dipod oriented in the Cu troughs. However, several other configurations close to this stable structure with tilted dipod and tripod orientations yield total binding energies per molecule which are only 10 meV (i.e., less than 5%) weaker. Due to the lack of additional information on the potential accuracy, we find that the minimization procedure has difficulty discriminating unequivocally between structures with a large number of molecules per unit cell and for which changes in molecular orientations do not sensitively modify the total energy in the cell. In order to recover the experimental structure we propose a (2×18) phase with 18 CF4 molecules per unit cell, deduced from the...

The phonon dispersion curves for monolayer Xe adsorbed on Cu(110) were measured along the {ovr {Gamma}}{ovr X} and {ovr {Gamma}}{ovr Y} directions using inelastic He scattering. The dispersion along these two orthogonal high-symmetry directions is fundamentally different as a consequence of the substrate anisotropy. Coupled dynamics calculations using a slab model are performed on the square low-order commensurate c(2{times}2) structure and on the (26{times}2) high-order commensurate phase of the Xe monolayer, the latter being stable at low temperature. The calculations allow a quantitative interpretation of the hybridization and avoided crossings between the longitudinal and perpendicular monolayer branches and the Rayleigh mode along {ovr {Gamma}}{ovr X}. They can also account for the unexpected behavior of the monolayer longitudinal mode along {ovr {Gamma}}{ovr Y}, revealing a different type of dynamical coupling between this monolayer branch and the longitudinally polarized Rayleigh mode of the substrate. This coupling is responsible for a polarization exchange by which both modes become susceptible to He scattering detection. {copyright} {ital 1997} {ital The American Physical Society}