Search

We present a coarse-grained (CG) model of a rodlike higher-order quadruplex with explicit monovalent salts, which was developed from radial distribution functions of an underlying reference atomistic molecular dynamics simulation using inverse Monte Carlo technique. This work improves our previous CG model and extends its applicability beyond the minimal salt conditions, allowing its use at variable ionic strengths. The strategies necessary for the model development are clearly explained and discussed. The effects of the number of stacked quadruplexes and varied salt concentration on the elasticity of the rodlike higher-order quadruplex structures are analyzed. The CG model reproduces the deformations of the terminal parts in agreement with experimental observations without introducing any special parameters for terminal beads and reveals slight differences in the rise and twist of the G-quartet arrangement along the studied biopolymer. The conclusions of our study can be generalized for other G-quartet-based structures., Competing Interests: The authors declare no competing financial interest.

The all-atomic force field Slipids (Stockholm Lipids) for lipid bilayers simulations has been extended to polyunsaturated lipids. Following the strategy adopted in the development of previous versions of the Slipids force field, the parametrization was essentially based on high-level ab initio calculations. Atomic charges and torsion angles related to polyunsaturated lipid tails were parametrized using structures of dienes molecules. The new parameters of the force field were validated in simulations of bilayers composed of seven polyunsaturated lipids. An overall good agreement was found with available experimental data on the areas per lipids, volumetric properties of bilayers, deuterium order parameters, and scattering form factors. Furthermore, simulations of bilayers consisting of highly polyunsaturated lipids and cholesterol molecules have been carried out. The majority of cholesterol molecules were found in a position parallel to bilayer normal with the hydroxyl group directed to the membrane surface, while a small fraction of cholesterol was found in the bilayer center parallel to the membrane plane. Furthermore, a tendency of cholesterol molecules to form chain-like clusters in polyunsaturated bilayers was qualitatively observed.

With the rapid development of computer power and wide availability of modelling software computer simulations of realistic models of lipid membranes, including their interactions with various molecular species, polypeptides and membrane proteins have become feasible for many research groups. The crucial issue of the reliability of such simulations is the quality of the force field, and many efforts, especially in the latest several years, have been devoted to parametrization and optimization of the force fields for biomembrane modelling. In this review, we give account of the recent development in this area, covering different classes of force fields, principles of the force field parametrization, comparison of the force fields, and their experimental validation. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg., (Copyright © 2016. Published by Elsevier B.V.)

To model large biomolecular systems, such as cell and organelles an atomistic description is not currently achievable and is not generally practical. Therefore, simplified coarse-grained (CG) modelling becomes a necessity. One of the most important cellular components is chromatin, a large DNA-protein complex where DNA is highly compacted. Recent progress in coarse graining modelling of the major chromatin components, double helical DNA and the nucleosome core particle (NCP) is presented. First, general principles and approaches allowing rigorous bottom-to-top generation of interaction potentials in the CG models are presented. Then, recent CG models of DNA are reviewed and their adequacy is benchmarked against experimental data on the salt dependence of DNA flexibility (persistence length). Furthermore, a few recent CG models of the NCP are described and their application for studying salt-dependent NCP-NCP interaction is discussed. An example of a multiscale approach to CG modelling of chromatin is presented where interactions and self-assembly of thousands of NCPs in solution are observed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We outline our coarse-graining strategy for linking micro- and mesoscales of soft matter and biological systems. The method is based on effective pairwise interaction potentials obtained in detailed ab initio or classical atomistic Molecular Dynamics (MD) simulations, which can be used in simulations at less accurate level after scaling up the size. The effective potentials are obtained by applying the inverse Monte Carlo (IMC) method [A. P. Lyubartsev and A. Laaksonen, Phys. Rev. E 52(4), 3730-3737 (1995)] on a chosen subset of degrees of freedom described in terms of radial distribution functions. An in-house software package MagiC is developed to obtain the effective potentials for arbitrary molecular systems. In this work we compute effective potentials to model DNA-protein interactions (bacterial LiaR regulator bound to a 26 base pairs DNA fragment) at physiological salt concentration at a coarse-grained (CG) level. Normally the IMC CG pair-potentials are used directly as look-up tables but here we have fitted them to five Gaussians and a repulsive wall. Results show stable association between DNA and the model protein as well as similar position fluctuation profile.

Accurate estimation of protein-carbohydrate binding energies using computational methods is a challenging task. Here we report the use of expanded ensemble molecular dynamics (EEMD) simulation with double decoupling for estimation of binding energies of hevein, a plant lectin with its monosaccharide and disaccharide ligands GlcNAc and (GlcNAc)2, respectively. In addition to the binding energies, enthalpy and entropy components of the binding energy are also calculated. The estimated binding energies for the hevein-carbohydrate interactions are within the range of ±0.5 kcal of the previously reported experimental binding data. For comparison, binding energies were also estimated using thermodynamic integration, molecular dynamics end point calculations (MM/GBSA) and the expanded ensemble methodology is seen to be more accurate. To our knowledge, the method of EEMD simulations has not been previously reported for estimating biomolecular binding energies.

We present a new force field parameter set for simulating alkanes. Its functional form and parameters are chosen to make it directly compatible with the AMBER94/99/12 family of force fields implemented in the available software. The proposed parameterization enables universal description of both the conformational and thermodynamic properties of linear, branched, and cyclic alkanes. Such unification is achieved by using two essential principles: (1) reduction of the Lennard-Jones radius for all sp3 carbons to 1.75Å; (2) separate optimization of Lennard-Jones well depths for carbons with different degree of substitution. The new parameter set may prove to be optimal for description of alkyl residues in a broad range of biomolecules, from amino acids to lipids with their extended linear tails.

Molecular dynamics (MD) simulations of glycylglycine dipeptide with transition metal ions (Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), and Zn(2+)) in aqueous solutions have been carried out to get an insight into the solvation structure, intermolecular interactions, and salt effects in these systems. The solvation structure and hydrogen bonding were described in terms of radial distribution function (RDF) and spatial distribution function (SDF). The dynamical properties of the solvation structure were also analyzed in terms of diffusion and residence times. The simulation results show the presence of a well-defined first hydration shell around the dipeptide, with water molecules forming hydrogen bonds to the polar groups of the dipeptide. This shell is, however, affected by the strong electric field of divalent metal ions, which at higher ion concentrations lead to the shift in the dipeptide-water RDFs. Higher salt concentrations lead also to increased residence times and slower diffusion rates. In general, smaller ions (Cu(2+), Zn(2+)) demonstrate stronger binding to dipeptide than the larger ones (Fe(2+), Mn(2+)). Simulations do not show any stronger association of peptide molecules indicating their dissolution in water. The above results may be of potential interest to future researchers on these molecular interactions.

In order to investigate structural and dynamical properties of local anesthetic articaine in a model lipid bilayer, a series of molecular dynamics simulations have been performed. Simulations were carried out for neutral and charged (protonated) forms of articaine inserted in fully hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer. For comparison purpose, a fully hydrated DMPC bilayer without articaine was also simulated. The length of each simulation was 200ns. Various properties of the lipid bilayer systems in the presence of both charged and uncharged forms of articaine taken at two different concentrations have been examined: membrane area per lipid, mass density distributions, order parameters, radial distribution functions, head group tilt, diffusion coefficients, electrostatic potential, etc, and compared with results of previous simulations of DMPC bilayer in the presence of lidocaine. It was shown that addition of both charged and neutral forms of articaine causes increase of the dipole electrostatic potential in the membrane interior., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The paper reviews our current studies on the experimentally induced cation compaction and aggregation in solutions of DNA and nucleosome core particles and the theoretical modelling of these processes using coarse-grained continuum models with explicit mobile ions and with all-atom molecular dynamics (MD) simulations. Recent experimental results on DNA condensation by cationic oligopeptides and the effects of added salt are presented. The results of MD simulations modelling DNA-DNA attraction due to the presence of multivalent ions including the polyamine spermidine and fragments of histone tails, which exhibit bridging between adjacent DNA molecules, are discussed. Experimental data on NCP aggregation, using recombinantly prepared systems are summarized. Literature data and our results of studying of the NCP solutions are compared with predictions of coarse-grained MD simulations, including the important ion correlation as well as bridging mechanisms. The importance of the results to chromatin folding and aggregation is discussed., (Copyright 2009 Elsevier B.V. All rights reserved.)

This paper describes an analysis of NMR dipolar couplings in a bilayer formed by dimyristoylphosphatidylcholine (DMPC). The couplings are calculated from a trajectory generated in a molecular dynamics (MD) simulation based on a realistic atom-atom interaction potential. The analysis is carried out employing a recently developed approach that focuses on the construction of the conformational distribution function. This approach is a combination of two models, the additive potential (AP) model and the maximum entropy (ME) method, and is therefore called APME. In contrast to the AP model, the APME procedure does not require an intuition-based choice of the functional form of the torsional potential and is, unlike the ME method, applicable to weakly ordered systems. The conformational distribution function for the glycerol moiety of the DMPC molecule derived from the APME analysis of the dipolar couplings is in reasonable agreement with the "true" distributions calculated from the trajectory. Analyses of dipolar couplings derived from MD trajectories can, in general, serve as guidelines for experimental investigations of bilayers and other complex biological systems.

Molecular dynamics computer simulations have been performed to investigate dynamical and structural properties of a lidocaine local anesthetic. Both charged and uncharged forms of the lidocaine molecule were investigated. Properties such as membrane area per lipid, diffusion, mass density, bilayer penetration and order parameters have been examined. An analysis of the lidocaine interaction with the lipid surrounding according to a simple mean field theory has also been performed. Almost all examined properties were found to depend on which of the two forms of lidocaine, charged or uncharged, is studied. The overall picture is a rather static behavior determined by the lipids for the charged molecules and more mobile situation of the uncharged form with higher diffusion and lower orientational and positional order.

A series of molecular dynamics simulations of dimyristoylphosphatidylcholine bilayers, with different levels of hydration and temperature, were performed to examine the influence of hydration on properties of lipid membranes. Structural and dynamical properties such as area per lipid, electron densities, order parameters for all CH bonds and water, diffusion, and reorientation autocorrelation functions were determined and were all found to be affected by changes in the hydration level. The simulations give an overall picture of the bilayer going to a more ordered state when the hydration level is reduced. Lipid headgroups were found to adopt an orientation more parallel to the membrane plane when the water content was decreased. Dynamical properties such as lipid diffusion and relaxation of reorientation time correlation functions were found to become slower with the removal of water. Our simulation results generally agree with experimental data in cases where such data are available. One important conclusion drawn is that while structural properties are affected only moderately dynamical properties are affected very strongly by a decrease of water content.

The Bead-Fourier path integral molecular dynamics technique introduced earlier [S. D. Ivanov, A. P. Lyubartsev, and A. Laaksonen, Phys. Rev. E 67 066710 (2003)] is applied for simulation of electrons in the simplest molecules: molecular hydrogen, helium atom, and their ions. Special attention is paid to the correct description of electrons in the core region of a nucleus. In an attempt to smooth the Coulomb potential at small distances, a recipe is suggested. The simulation results are in excellent agreement with the analytical solution for the "harmonic helium atom", as well as with the vibrational potential of the H(2) molecule and He ionization energies. It is demonstrated, that the Bead-Fourier path integral molecular dynamics technique is able to provide the accuracy required for the description of electron structure and chemical bonds in cases when electron exchange effects need not be taken into account.

Car-Parrinello molecular dynamics simulations of a hydroxyl radical in liquid water have been performed. Structural and dynamical properties of the solvated structure have been studied in details. The partial atom-atom radial distribution functions for the hydrated hydroxyl do not show drastic differences with the radial distribution functions for liquid water. The OH is found to be a more active hydrogen bond donor and acceptor than the water molecule, but the accepted hydrogen bonds are much weaker than for the hydroxide OH- ion. The first solvation shell of the OH is less structured than the water's one and contains a considerable fraction of water molecules that are not hydrogen bonded to the hydroxyl. Part of them are found to come closer to the solvated radical than the hydrogen bonded molecules do. The lifetime of the hydrogen bonds accepted by the hydroxyl is found to be shorter than the hydrogen bond lifetime in water. A hydrogen transfer between a water molecule and the OH radical has been observed, though it is a much rarer event than a proton transfer between water and an OH- ion. The velocity autocorrelation power spectrum of the hydroxyl hydrogen shows the properties both of the OH radical in clusters and of the OH- ion in liquid.

Four different molecular dynamics (MD) simulations have been performed for infinitely long ordered DNA molecules with different counterions, namely the two natural polyamines spermidine(3+) (Spd3+) and putrescine(2+) (Put2+), the synthetic polyamine diaminopropane(2+) (DAP2+), and the simple monovalent cation Na+. All systems comprised a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charge. The simulation setup mimics the DNA state in oriented DNA fibers, previously studied using NMR and other experimental methods. In this paper the interplay between polyamine binding and local DNA structure is analyzed by investigating how and if the minor groove width of DNA depends on the presence and dynamics of the counterions. The results of the MD simulations reveal principal differences in the polyamine-DNA interactions between the natural [spermine(4+), Spd3+, Put2+] and the synthetic (DAP2+) polyamines.

A new method of calculating absolute free energies is presented. It was developed as an extension to the expanded ensemble molecular dynamics scheme and uses probability density estimation to continuously optimize the expanded ensemble parameters. The new method is much faster as it removes the time-consuming and expertise-requiring step of determining balancing factors. Its efficiency and accuracy are demonstrated for the dissolution of three qualitatively very different chemical species in water: methane, ionic salts, and benzylamine. A recently suggested optimization scheme by Wang and Landau [Phys. Rev. Lett. 86, 2050 (2001)] was also implemented and found to be computationally less efficient than the proposed adaptive expanded ensemble method., ((c) 2004 American Institute of Physics.)

Four different molecular dynamics (MD) simulations have been performed for ordered DNA decamers, d(5'-ATGCAGTCAG)*d(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine3+ (Spd3+) and putrescine2+ (Put2+), the synthetic polyamine diaminopropane2+ (DAP2+) and Na+. The simulation set-up corresponds to an infinite array of parallel DNA mimicking the state in oriented DNA fibers or crystals. This work describes general properties of polyamine and Na+ binding to DNA. Simulated diffusion coefficients show satisfactory agreement with experimental NMR diffusion data of comparable systems. The interaction of the polyamines with DNA is dynamic in character and the cations mostly form short-lived contacts with the electronegative binding sites of DNA. Polyamines, Na+ and water interact most frequently with the charged phosphate atoms with preference for association from the minor groove side with O1P over O2P. There is a strong anti-correlation in the cation binding to the electronegative groups of DNA, i.e. the presence of a cation near one of the DNA sites repels other cations from binding to this and to the other sites separated by <7.5 A from each other. In contrast to the other polyamines, DAP2+ is able to form 'bridges' connecting neighboring phosphate groups along the DNA strand. A small fraction of DAP2+ and Put2+ can be found in the major grooves, while Spd3+ is absent there. The results of the MD simulations reveal principal differences in the polyamine-DNA interactions between the natural (Spd3+, Put2+ and spermine4+) and synthetic (DAP2+) polyamines.