Calculation of the surface tension of planar interfaces by molecular simulations: from Lennard-Jones fluids to binary mixtures

The relative longevity of the research in the field of the molecular simulations of the liquid–vapour interfaces of Lennard-Jones (LJ) particles can be explained by the dependence of the surface tension on many methodological factors. After a few illustrations on the parameters that can impact the results of surface tension on the LJ interfaces, we establish the ability of the current methodologies to quantitatively predict the surface tension of various liquid–vapour interfaces of pure components at different temperatures. We also show that the methods perform very well for the reproduction of the interfacial tension of binary mixtures in a wide range of pressures.     

Adsorption and structure of benzene confined in disordered porous carbons: effect of pore heterogeneity and surface chemistry

Molecular simulations are used to study the adsorption of benzene at 300?K in atomistic models of disordered nanoporous carbons. These models, named as CS400, CS1000 and CS1000a, differ in density and chemical compositions, and reproduce the morphological and topological features present in real nanoporous carbons. We found that the adsorption phenomena depend upon the local structure of nanoporous carbons. To understand the effect of surface chemistry on adsorption and structure of confined benzene, functional groups (–COOH and –C=O) were added to these models. The presence of functional groups led to the onset of adsorption process at a low pressure. The carboxyl groups (–COOH) have a greater impact on adsorption as compared to carbonyl (–C=O) groups. The CS1000a models have wide micropores and thus it exhibits a jump in adsorption isotherm. The jump shifts towards lower pressure on the addition of functional groups, with –COOH groups showing a larger shift. The presence of functional groups also increases the isosteric heat of adsorption, with –COOH groups showing higher values. The coulombic contribution to total fluid–wall interaction energy is higher for –COOH functional groups and decreases on increasing pressure. Benzene confined in CS1000a models exhibit a liquid-like structure.     

Molecular dynamics studies in nanoscale liquid structures: geometry and thermal effects on nanojet development

Conventional macroscopic jet theory relies heavily on experimental correlations which cannot be easily extended to the nanoscale regime. Moreover, the fluid dynamic effects at small length scales and their contribution to the development of nanoscale liquid structures are fundamentally different from their macroscopic counterparts. This coupled with the high spatial and temporal resolution requirements at nanoscale domains make molecular dynamics (MD) an excellent tool for studying such structures. In this study, the formation and breakup of nanojets (NJs) developing from high pressure into vacuum is investigated using MD based on non-Hamiltonian formulations. By ejecting the equilibrated argon atoms through various nozzle geometries and diameters, nanoscale jet flows were generated. The dependence of the jet structure on nozzle geometry and diameter is studied. The influence of geometry on NJ formation is also studied along with issues involved in the equilibration and thermostat coupling parameter. Various thermostats are compared to understand the role they play in MD simulations of liquid nanostructures. Tuning of the thermostat coupling parameter has also been discussed. The jet breakup phenomenon is analysed and a comparative study, vis-à-vis, well-established continuum and stochastic models, is attempted.     

NMR evidence of hydrogen bonding in 1-ethyl-3-methylimidazolium-tetrafluoroborate room temperature ionic liquid

The 1-ethyl-3-methylimidazolium-tetrafluoroborate (EMI–BF₄) room temperature ionic liquid was investigated with NMR techniques. Diffusion coefficients measured at temperatures ranging from 300 to 360 K indicate that phase-change occurred in the vicinity of 333 K, which is supported by ¹¹B quadrupolar relaxation rates. This phase change is ascribed to the transformation of the diffusion particle from ‘discrete ion-pair’ to ‘individual ion’ at temperatures above 335 K due to decomposition of the EMI–BF₄ ion pair. Analysis of the ¹³C dipole–dipole relaxation rates identifies the formation of hydrogen bond (C2HF) between the counterions, EMI⁺ and BF₄ ⁻. This hydrogen bonding may have significant contribution to the higher viscosity of this ionic liquid in comparison with the EMI–AlCl₄ ionic liquid at corresponding temperatures.     

Molecular dynamics simulation of thermal conductivity of an argon liquid layer confined in nanospace

Molecular dynamics simulations were used to study the thermal conductivity of liquid argon ultra thin films confined between two plates spaced several nanometres apart. The research focused on the dependence of the liquid argon thermal conductivity on the liquid layer thickness and the interaction between liquid and solid. The results show that the thermal conductivity of liquid argon ultra thin films confined between two plates depends on the distance between the two plates and the existence of solid-like liquid layering at the liquid–solid interface and the average migration frequency of all liquid molecules. Stronger interactions between the liquid and the solid resulted in a larger number of atoms in the solid-like liquid layer along the surface and hence smaller thermal resistance between the liquid and the solid. However, as the strength of the interaction with the solid increased, the thermal conductivity was reduced due to fewer atoms near the hot solid boundary and less molecular migration.     

Spatial heterogeneity in landscape structure influences dispersal and genetic structure: empirical evidence from a grasshopper in an agricultural landscape

Dispersal may be strongly influenced by landscape and habitat characteristics that could either enhance or restrict movements of organisms. Therefore, spatial heterogeneity in landscape structure could influence gene flow and the spatial structure of populations. In the past decades, agricultural intensification has led to the reduction in grassland surfaces, their fragmentation and intensification. As these changes are not homogeneously distributed in landscapes, they have resulted in spatial heterogeneity with generally less intensified hedged farmland areas remaining alongside streams and rivers. In this study, we assessed spatial pattern of abundance and population genetic structure of a flightless grasshopper species, Pezotettix giornae, based on the surveys of 363 grasslands in a 430‐km² agricultural landscape of western France. Data were analysed using geostatistics and landscape genetics based on microsatellites markers and computer simulations. Results suggested that small‐scale intense dispersal allows this species to survive in intensive agricultural landscapes. A complex spatial genetic structure related to landscape and habitat characteristics was also detected. Two P. giornae genetic clusters bisected by a linear hedged farmland were inferred from clustering analyses. This linear hedged farmland was characterized by high hedgerow and grassland density as well as higher grassland temporal stability that were suspected to slow down dispersal. Computer simulations demonstrated that a linear‐shaped landscape feature limiting dispersal could be detected as a barrier to gene flow and generate the observed genetic pattern. This study illustrates the relevance of using computer simulations to test hypotheses in landscape genetics studies.     

The fixation probability of a beneficial allele in a population dividing by binary fission

We derive formulae for the fixation probability, P, of a rare benefical allele segregating in a population of fixed size which reproduces by binary fission, in terms of the selection coefficient for the beneficial allele, s. We find that an earlier result P 4s does not depend on the assumption of binary fission, but depends on an assumption about the ordering of events in the life cycle. We find that P 2s for mutations occurring during chromosome replication and P 2.8s for mutations occurring at random times between replication events.     

Effect of replacing [NTf2] by [PF6] anion on the [BMIm][NTf2] ionic liquid confined by gold

The effect of replacing bis(trifluoromethylsulphonyl)imide ([NTf₂]) by hexafluorophosphate ([PF₆]) in room temperature ionic liquid (IL) 1-butyl-3-methylimidazolium bis(trifluoromethylsulphonyl)imide ([BMIm][NTf₂]) confined between two gold interfaces is herein reported through molecular dynamics simulations using all-atom non-polarisable force-fields. Five systems were studied ranging from pure [BMIm][NTf₂] to pure [BMIm][PF₆], with [PF₆] molar fractions of 0, 0.125, 0.25, 0.375 and 0.5. Special attention was drawn to investigate the impact of the [PF₆] anion on the IL, in particular on the first layers of the liquid in close contact with the solid gold surface.     

Opening of the ADP-bound active site in the ABC transporter ATPase dimer: evidence for a constant contact, alternating sites model for the catalytic cycle

ABC transporters are ubiquitous, ATP-dependent transmembrane pumps. The mechanism by which ATP hydrolysis in the nucleotide-binding domain (NBD) effects conformational changes in the transmembrane domain that lead to allocrite translocation remains largely unknown. A possible aspect of this mechanism was suggested by previous molecular dynamics simulations of the MJ0796 NBD dimer, which revealed a novel, nucleotide-dependent intrasubunit conformational change involving the relative rotation of the helical and catalytic subdomains. Here, we find that in four of five simulations of the ADP/ATP-bound dimer, the relative rotation of the helical and catalytic subdomains in the ADP-bound monomer results in opening of the ADP-bound active site, probably sufficient or close to sufficient to allow nucleotide exchange. We also observe that in all five simulations of the ADP/ATP-bound dimer, the intimate contact of the LSGGQ signature sequence with the ATP gamma-phosphate is weakened by the intrasubunit conformational change within the ADP-bound monomer. We discuss how these results support a constant contact model for the function of the NBD dimer in contrast to switch models, in which the NBDs are proposed to fully disassociate during the catalytic cycle.     

Monte Carlo simulations of the peptide recognition at the consensus binding site of the constant fragment of human immunoglobulin G: the energy landscape analysis of a hot spot at the intermolecular interface

Monte Carlo simulations of molecular recognition at the consensus binding site of the constant fragment (Fc) of human immunoglobulin G (Ig) protein have been performed to analyze structural and thermodynamic aspects of binding for the 13-residue cyclic peptide DCAWHLGELVWCT. The energy landscape analysis of a hot spot at the intermolecular interface using alanine scanning and equilibrium-simulated tempering dynamics with the simplified, knowledge-based energy function has enabled the role of the protein hot spot residues in providing the thermodynamic stability of the native structure to be determined. We have found that hydrophobic interactions between the peptide and the Met-252, Ile-253, His-433, and His-435 protein residues are critical to guarantee the thermodynamic stability of the crystallographic binding mode of the complex. Binding free energy calculations, using a molecular mechanics force field and a solvation energy model, combined with alanine scanning have been conducted to determine the energetic contribution of the protein hot spot residues in binding affinity. The conserved Asn-434, Ser-254, and Tyr-436 protein residues contribute significantly to the binding affinity of the peptide-protein complex, serving as an energetic hot spot at the intermolecular interface. The results suggest that evolutionary conserved hot spot protein residues at the intermolecular interface may be partitioned in fulfilling thermodynamic stability of the native binding mode and contributing to the binding affinity of the complex.     

Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations

Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported. Clustering analysis allowed identifying the most populated conformers present during the MD simulation, which were used as starting models to perform docking calculations with five DD2-HDAC6 inhibitors: Cay10603 (CAY), Rocilinostat (RCT), Tubastatin A (TBA), Tubacin (TBC), and Nexturastat (NXT), and then were also submitted to 100-ns-long MD simulations. Docking calculations revealed that the five inhibitors bind at the DD2-HDAC6 binding site with the lowest binding free energy, the same binding mode is maintained along the 100-ns-long MD simulations. Overall, our results provide structural information about the molecular flexibility of apo and holo DD2-HDAC6 states as well as insight of the map of interactions between DD2-HDAC6 and five well-known DD2-HDAC6 inhibitors allowing structural details to guide the drug design. Finally, we highlight the importance of combining different theoretical approaches to provide suitable structural models for structure-based drug design.     

Towards the identification of the allosteric Phe-binding site in phenylalanine hydroxylase

The enzyme phenylalanine hydroxylase (PAH) is defective in the inherited disorder phenylketonuria. PAH, a tetrameric enzyme, is highly regulated and displays positive cooperativity for its substrate, Phe. Whether Phe binds to an allosteric site is a matter of debate, despite several studies worldwide. To address this issue, we generated a dimeric model for Phe–PAH interactions, by performing molecular docking combined with molecular dynamics simulations on human and rat wild-type sequences and also on a human G46S mutant. Our results suggest that the allosteric Phe-binding site lies at the dimeric interface between the regulatory and the catalytic domains of two adjacent subunits. The structural and dynamical features of the site were characterized in depth and described. Interestingly, our findings provide evidence for lower allosteric Phe-binding ability of the G46S mutant than the human wild-type enzyme. This also explains the disease-causing nature of this mutant.     

Exploring the structure characteristics and major channels of cytochrome P450 2A6, 2A13, and 2E1 with pilocarpine

The majority of cytochromes P450 play a critical role in metabolism of endogenous and exogenous substrates, some of its products are carcinogens. Therefore, inhibition of P450 enzymes activity can promote the detoxification and elimination of chemical carcinogens. In this study, molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed to explore the structure features and channel dynamics of three P450 isoforms 2A6, 2A13, and 2E1 bound with the common inhibitor pilocarpine. The binding free energy results combined with the PMF calculations give a reasonable ranking of binding affinity, which are consistent with the experimental data. Our results uncover how a sequence divergence of different CYP2 enzymes causes individual variations in major channel selections. On the basis of channel bottleneck and energy decomposition analysis, we propose a gating mechanism of their respective major channels in three enzymes, which may be attributed to a reversal of Phe209 in CYP2A6/2A13, as well as the rotation of Phe116 and Phe298 in CYP2E1. The hydrophobic residues not only make strong hydrophobic interactions with inhibitor, but also act as gatekeeper to regulate the opening of channel. The present study provides important insights into the structure–function relationships of three cytochrome P450s and the molecular basis for development of potent inhibitors.     

In silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitors

The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.     

Engineering an Mg2+ site to replace a structurally conserved arginine in the catalytic center of histidyl-tRNA synthetase by computer experiments

Histidyl-tRNA synthetase (HisRS) differs from other class II aminoacyl-tRNA synthetases (aaRS) in that it harbors an arginine at a position where the others bind a catalytic Mg²⁺ ion. In computer experiments, four mutants of HisRS from Escherichia coli were engineered by removing the arginine and introducing a Mg²⁺ ion and residues from seryl-tRNA synthetase (SerRS) that are involved in Mg²⁺ binding. The mutants recreate an active site carboxylate pair conserved in other class II aaRSs, in two possible orders: Glu-Asp or Asp-Glu, replacing Glu-Thr in native HisRS. The mutants were simulated by molecular dynamics in complex with histidyl-adenylate. As controls, the native HisRS was simulated in complexes with histidine, histidyl-adenylate, and histidinol. The native structures sampled were in good agreement with experimental structures and biochemical data. The two mutants with the Glu-Asp sequence showed significant differences in active site structure and Mg²⁺ coordination from SerRS. The others were more similar to SerRS, and one of them was analyzed further through simulations in complex with histidine, and His+ATP. The latter complex sampled two Mg²⁺ positions, depending on the conformation of a loop anchoring the second carboxylate. The lowest energy conformation led to an active site geometry very similar to SerRS, with the principal Mg²⁺ bridging the α- and β-phosphates, the first carboxylate (Asp) coordinating the ion through a water molecule, and the second (Glu) coordinating it directly. This mutant is expected to be catalytically active and suggests a basis for the previously unexplained conservation of the active site Asp-Glu pair in class II aaRSs other than HisRS. Proteins 32:362–380, 1998. © 1998 Wiley-Liss, Inc.     

Formation of one-dimensional Pt structures in VET-type zeolites: a combined force field and first principles study

The viability of forming stable one-dimensional Pt structures inside the pores of VET-type zeolites is evaluated in this study by using molecular simulations. The resulting nanostructures were optimised and analysed as formed both inside and outside the zeolite. The results show that, theoretically, it is possible to obtain thermally stable ultrathin nanowires in VET zeolites with a low Si/Al ratio using high temperatures during formation. The results also show that the structures obtained with the pcff force field for the ultrathin nanowires are qualitatively similar to those obtained after geometric optimisation with DFT.