Free Energy Profile of Domain Movement in Ligand-Free Citrate Synthase

Citrate synthase plays a fundamental role in the metabolic cycle of the cell. Its catalytic mechanism is complex involving the binding of two substrates that cause a domain movement. In this paper, we used classical molecular dynamics simulations and umbrella sampling simulations to determine the potential of mean force along a reaction coordinate for the domain movement in ligand-free citrate synthase from pig (Sus Scrofa). The results show that at 293 K, the closed-domain conformation has a ~4 kbT higher energy than the open-domain conformation. In a simple two-state model, this difference means that the enzyme spends 98% of the time in the open-domain conformation ready to receive the substrate, oxaloacetate, rather than the closed-domain conformation where the binding site would be inaccessible to the substrate. Given that experimental evidence indicates that the binding of oxaloacetate induces at least partial closure, this would imply an induced-fit mechanism which we argue is applicable to all enzymes with a functional domain movement for reasons of catalytic efficiency. A barrier of 4 kbT gives an estimation of the mean first passage time in the range 1-10 microseconds

A new 2,2,2-triflouroethanol model for molecular dynamics simulations

A new model for 2,2,2-trifluoroethano1 is proposed. It is a 7-atom model with the methylene group treated as an united atom. The model was optimized to reproduce the physicochemical properties of the pure liquid. The properties of the new model were compared with the available experimental data over a range of temperatures. Furthermore, mixtures with the SPC water model were simulated to assess the ability to reproduce available thermodynamic and kinetic data as well as dielectric properties. The model provides a good agreement with experimental data for the neat liquid and for mixtures with water

Strings-to-rings transition and antiparallel dipole alignment in two-dimensional methanols

Structural order emerging in the liquid state necessitates a critical degree of anisotropy of the molecules. For example, liquid crystals and Langmuir monolayers require rod- or disc-shaped and long-chain amphiphilic molecules, respectively, to break the isotropic symmetry of liquids. In this Letter we present results from molecular dynamics simulations demonstrating that in two-dimensional liquids, a significantly smaller degree of anisotropy is sufficient to allow structural organization. In fact, the condensed phase of the smallest amphiphilic molecule, methanol, confined between two, or adsorbed on, graphene sheets forms a monolayer characterized by long chains of molecules. Intrachain interactions are dominated by hydrogen bonds, whereas interchain interactions are dispersive. Upon a decrease in density toward a gaslike state, these strings are transformed into rings. The two-dimensional liquid phase of methanol undergoes another transition upon cooling; in this case, the order–disorder transition is characterized by a low-temperature phase in which the hydrogen bond dipoles of neighboring strings adopt an antiparallel orientation

Understanding the Interaction of Block Copolymers with DMPC Lipid Bilayer using Coarse-Grained Molecular Dynamics Simulations

In this paper, we present a computational model of the adsorption and percolation mechanism of poloxamers (poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) triblock copolymers) across a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer. A coarse-grained model was used to cope with the long time scale of the percolation process. The simulations have provided details of the interaction mechanism of Pluronics with lipid bilayer. In particular, the results have shown that polymer chains containing a PPO block with a length comparable to the DMPC bilayer thickness, such as P85, tends to percolate across the lipid bilayer. On the contrary, Pluronics with a shorter PPO chain, such as L64 and F38, insert partially into the membrane with the PPO block part while the PEO blocks remain in water on one side of the lipid bilayer. The percolation of the polymers into the lipid tail groups reduces the membrane thickness and increases the area per lipid. These effects are more evident for P85 than L64 or F38. Our findings are qualitatively in good agreement with published small-angle X-ray scattering experiments that have evidenced a thinning effect of Pluronics on the lipid bilayer as well as the role of the length of the PPO block on the permeation process of the polymer through the lipid bilayer. Our theoretical results complement the experimental data with a detailed structural and dynamic model of poloxamers at the interface and inside the lipid bilayer

Hybrid Particle-Field Coarse-Grained Models for Biological Phospholipids

In the framework of a recently developed scheme for a hybrid particle-field simulation technique where self-consistent field theory (SCF) and molecular dynamics (MD) are combined [J. Chem. Phys. 2009, 130, 214106], specific coarse-grained models for phospholipids and water have been developed. We optimized the model parameters, which are necessary in evaluating the interactions between the particles and the density fields, so that the coarse-grained model can reproduce the structural properties of the reference particle-particle simulations. The development of these specific coarse-grained models suitable for hybrid particle-field simulations opens the way toward simulations of large-scale systems employing models with chemical specificity, especially for biological systems. © 2011 American Chemical Society

Spontaneous insertion of carbon nanotube bundles inside biomembranes: a hybrid particle-field coarse-grained molecular dynamics study

The processes of CNTs bundle formation and insertion/rearrangement inside lipid bilayers, as models of cellular membranes, is described and analyzed in details using simulations on the microsecond scale. Molecular Dynamics simulations employing hybrid particle-field models (MD–SCF) show that during the insertion process lipid molecules coat bundles surfaces. The distortions of bilayers are more pronounced for systems undergoing to insertion of bundles made of longer CNTs. In particular, when the insertion occurs in perpendicular orientation, adsorption of lipids on CNTs surfaces promotes a transient poration. This result suggests mechanism of membrane disruption operated by bundles causing the formation of solvent-rich pockets

Structure, dynamics, and function of the monooxygenase P450 BM-3: insights from computer simulations studies

The monooxygenase P450 BM-3 is a NADPH-dependent fatty acid hydroxylase enzyme isolated from soil bacterium Bacillus megaterium. As a pivotal member of cytochrome P450 superfamily, it has been intensely studied for the comprehension of structure-dynamics-function relationships in this class of enzymes. In addition, due to its peculiar properties, it is also a promising enzyme for biochemical and biomedical applications. However, despite the efforts, the full understanding of the enzyme structure and dynamics is not yet achieved. Computational studies, particularly molecular dynamics (MD) simulations, have importantly contributed to this endeavor by providing new insights at an atomic level regarding the correlations between structure, dynamics, and function of the protein. This topical review summarizes computational studies based on MD simulations of the cytochrome P450 BM-3 and gives an outlook on future directions

Design of a recombinant plasmids encoding single guide RNA for Cas9- mediated gene activation of integrin alpha v beta 3 in cells

Alpha v beta 3 integrin is a promising target for anticancer therapy. In the present study, we constructed recombinant plasmids aimed at enhancing the expression of integrin alpha 5 beta 3 via a CRISPR/Cas9-mediated gene activation system. These plasmids are designed to creation of a cell line with integrin overexpression for testing new drugs

Molecular properties of astaxanthin in water/ethanol solutions from computer simulations

Astaxanthin (AXT) is a reference model of xanthophyll carotenoids, which is used in medicine and food industry, and has potential applications in nanotechnology. Because of its importance, there is a great interest in understanding its molecular properties and aggregation mechanism in water and mixed solvents. In this paper, we report a novel model of AXT for molecular dynamics simulation. The model is used to estimate different properties of the molecule in pure solutions and in water/ethanol mixtures. The calculated diffusion coefficients of AXT in pure water and ethanol are (3.22+/- 0.01)10^{-6} cm^{2}s^{-1} and (2.7+/-0.4) 10^{-6} cm^{2}s^{-1}, respectively. Our simulations also show that the content of water plays a clear effect on the morphology of the AXT aggregation in water/ethanol mixture. In up to 75\% (v/v) water concentration, loosely connected network of dimers and trimers, and two-dimensional array structures are observed. At higher water concentrations, AXT molecules form more compact three-dimensional structures that are preferentially solvated by the ethanol molecules. The ethanol preferential binding and the formation of a well connected hydrogen bonding network on these AXT clusters, suggest that such preferential solvation can play an important role in controlling the aggregate structure