Molecular dynamics simulation study on the structures of fascin mutants

Fascin is a filamentous actin (F-actin) bundling protein, which cross-links F-actin into bundles and becomes an important component of filopodia on the cell surface. Fascin is overexpressed in many types of cancers. The mutation of fascin affects its ability to bind to F-actin and the progress of cancer. In this paper, we have studied the effects of residues of K22, K41, K43, K241, K358, K399, and K471 using molecular dynamics (MD) simulation. For the strong-effect residues, that is, K22, K41, K43, K358, and K471, our results show that the mutation of K to A leads to large values of root mean square fluctuation (RMSF) around the mutated residues, indicating those residues are important for the flexibility and thermal stability. On the other hand, based on residue cross-correlation analysis, alanine mutations of these residues reinforce the correlation between residues. Together with the RMSF data, the local flexibility is extended to the entire protein by the strong correlations to influence the dynamics and function of fascin. By contrast, for the mutants of K241A and K399A those do not affect the function of fascin, the RMSF data do not show significant differences compared with wild-type fascin. These findings are in a good agreement with experimental studies.     

Molecular dynamics simulation of the atomistic monolayer structures of N-acyl amino acid-based surfactants

Abstract

Atomic molecular dynamics simulations have been performed on the monolayer systems of N-acyl amino acid-based surfactants. The role of intermolecular hydrogen bonds and ionic side chain length of dicarboxylate surfactants were investigated through radial and spatial distribution functions. It was found that the hydrogen bonding capability between surfactants was the major factor determining the surface area each surfactant could occupy. Tighter packing of surfactants would lead to a weaker interaction with water molecule, and the protonation of carboxylate groups resulted in stronger inter-surfactant interactions. The hydrogen bonds with water molecules were found to prevail between the carboxylate groups, and regular cage-like water distributions surrounding the surfactant headgroups were seen. The introduction of divalent ions leads to a significant increase of counterion binding, and their intramolecular and intermolecular bindings of calcium ions were also well characterised. The intramolecular chelation of calcium ions was found impossible between the carboxylate groups for N-acyl glutamate due to its flexible side chain.     

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

The article reviews the application of biomolecular simulation methods to understand the structure, dynamics and interactions of nucleic acids with a focus on explicit solvent molecular dynamics simulations of guanine quadruplex (G-DNA and G-RNA) molecules. While primarily dealing with these exciting and highly relevant four-stranded systems, where recent and past simulations have provided several interesting results and novel insight into G-DNA structure, the review provides some general perspectives on the applicability of the simulation techniques to nucleic acids.     

Molecular dynamics simulation and steered molecular dynamics simulation on irisin dimers

Irisin is found closely associated with promoting the browning of beige fat cells in white adipose tissue. The crystal structure reveals that irisin forms a continuous inter-subunit β-sheet dimer. Here, molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation were performed to investigate the dissociation process and the intricate interactions between the two irisin monomers. In the process of MD, the interactions between the monomers were roughly analyzed through the average numbers of both hydrophobic contacts and H-bonds. Then, SMD was performed to investigate the accurate interaction energy between the monomers. By the analysis of dissociation energy, the van der Waals (vdW) force was identified as the major energy to maintain the dimer structure, which also verified the results of MD simulation. Meanwhile, 11 essential residues were discovered by the magnitude of rupture force during dissociation. Among them, residues Arg75, Glu79, Ile77, Ala88, and Trp90 were reported in a previous study using the method of mutagenesis and size exclusion chromatography, and several new important residues (Arg72, Leu74, Phe76, Gln78, Val80, and Asp91) were also identified. Interestingly, the new important residues that we discovered and the important residues that were reported are located in the opposite side of the β-sheet of the dimer.     

Molecular dynamics simulation of silicate glasses

Summary Although the structure of glasses is not really accessible by experimental methods, molecular dynamics is a very useful alternative, as we have tried to demonstrate in this chapter. The simulations reproduce the broad macroscopic features found in these glasses, both structural and transport-related, providing a basis for the more detailed atomic scale features found in the simulated structures. An understanding of important aspects of alkali ion transport, such as the mixed alkali effect and anomalous behaviour in some alumino-silicates, can thus be approached from the atomistic pictures of the glasses produced by the simulations. Although there is room for improvements to the potential models available, it should be clear that the further application of computer simulation methods, such as molecular dynamics, promises to provide much needed advances in glass science and engineering.     

Oligoglycine surface structures: molecular dynamics simulation

The full-atomic molecular dynamics (MD) simulation of adsorption mode for diantennary oligoglycines [H-Gly4-NH(CH2)5]2 onto graphite and mica surface is described. The resulting structure of adsorption layers is analyzed. The peptide second structure motives have been studied by both STRIDE (structural identification) and DSSP (dictionary of secondary structure of proteins) methods. The obtained results confirm the possibility of polyglycine II (PGII) structure formation in diantennary oligoglycine (DAOG) monolayers deposited onto graphite surface, which was earlier estimated based on atomic-force microscopy measurements.     

Molecular dynamics simulation of hydration in myoglobin

This study was carried out to evaluate the stability of the 89 bound water molecules that were observed in the neutron diffraction study of CO myoglobin. The myoglobin structure derived from the neutron analysis was used as the starting point in the molecular dynamics simulation using the software package CHARMM. After solvation of the protein, energy minimization and equilibration of the system, 50 ps of Newtonian dynamics was performed. This data showed that only 4 water molecules are continously bound during the length of this simulation while the other solvent molecules exhibit considerable mobility and are breaking and reforming hydrogen bonds with the protein. At any instant during the simulation, 73 of the hydration sites observed in the neutron structure are occupied by water. © 1995 Wiley-Liss, Inc.     

Molecular dynamics simulation of intrinsically disordered proteins

Intrinsically disordered proteins are biomolecules that do not have a definite 3D structure; therefore, their dynamical simulation cannot start from a known list of atomistic positions, such as a Protein Data Bank file. We describe a method to start a computer simulation of these proteins. The first step of the procedure is the creation of a multi-rod configuration of the molecule, derived from its primary sequence. This structure is dynamically evolved in vacuo until its gyration radius reaches the experimental average value; at this point solvent molecules, in explicit or implicit implementation, are added to the protein and a regular molecular dynamics simulation follows. We have applied this procedure to the simulation of tau, one of the largest totally disordered proteins.     

Molecular dynamics simulation of a phosphatidylglycerol membrane

Although molecular dynamics simulations are an important tool for studying membrane systems, relatively few simulations have used anionic lipids. This paper reports the first simulation of a pure phosphatidylglycerol (PG) bilayer. The properties of this equilibrated palmitoyloleoylphosphatidylglycerol membrane agree with experimental observations of PG membranes and with previous simulations of monolayers and mixed bilayers containing PG lipids. These simulations also provide interesting insights into hydrogen bonding interactions in PG membranes. This equilibrated membrane will be a useful starting point for simulations of membrane proteins interacting with PG lipids.     

Molecular dynamics simulation of a phospholipid membrane

We present the results of molecular dynamics (MD) simulations of a phospholipid membrane in water, including full atomic detail. The goal of the simulations was twofold: first we wanted to set up a simulation system which is able to reproduce experimental results and can serve as a model membrane in future simulations. This goal being reached it is then further possible to gain insight in to those properties that are experimentally more difficult to access. The system studied is dipalmitoylphosphatidylcholine/water, consisting of 5408 atoms. Using original force field parameters the membrane turned out to approach a gel-like state. With slight changes of the parameters, the system adopted a liquid-crystalline state. Separate 80 ps runs were performed on both the gel and liquid-crystalline systems. Comparison of MD results with reliable experimental data (bilayer repeat distance, surface area per lipid, tail order parameters, atom distributions) showed that our simulations, especially the one in the liquid-crystalline phase, can serve as a realistic model for a phospholipid membrane. Further analysis of the trajectories revealed valuable information on various properties. In the liquid-crystalline phase, the interface turns out to be quite diffuse, with water molecules penetrating into the bilayer to the position of the carbonyl groups. The 10–90% width of the interface turns out to be 1.3 nm and the width of the hydrocarbon interior 3.0 nm. The headgroup dipoles are oriented at a small angle with respect to the bilayer plane. The resulting charge distribution is almost completely cancelled by the water molecules. The electron density distribution shows a large dip in the middle of the membrane. In this part the tails are more flexible. The mean life time between dihedral transitions is 20 ps. The average number of gauche angles per tail is 3.5. The occurrence of kinks is not a significant feature.Abbreviations MD molecular dynamics - DPPC dipalmitoylphosphatidylcholine - SPC simple point charges - DPPE dipalmitoylphosphatidylethanolamine Correspondence to: H. J. C. Berendsen     

Molecular dynamics simulation of shell-symmetric Pd nanoclusters

The melting behaviour of Palladium (Pd) isolated shell-symmetric cubooctahedron and icosahedron nanoclusters, both consisting of 309 atoms, were simulated by Molecular Dynamics (MD) simulation, using the Sutton-Chen many-body potential (SC) for the interaction between the Pd atoms. The thermal, structural and dynamic properties were calculated for the Pd nanoclusters along the heating process. The cubooctahedron nanocluster melts around 1040 K, much lower than the melting point of bulk Pd system (1828.05 K). The icosahedron nanocluster melts around 1070 K. Furthermore, structural and dynamic evidence is found for the pre-melting of the nanoclusters. The outer two shells of the shell-symmetric nanocluster melt prior to their homogeneous melting of the whole nanoclusters.     

Molecular dynamics simulation of truncated bovine adrenodoxin

The 128 amino acid long soluble protein adrenodoxin (Adx) is a typical member of the ferredoxin protein family that are electron carrier proteins with an iron-sulfur cofactor. Adx carries electrons from adrenodoxin reductase (AdR) to cytochrome P450s. Its binding modes to these proteins were previously characterized by site-directed mutagenesis, by X-ray crystallography for the complex Adx:AdR, and by NMR. However, no clear evidence has been provided for the driving force that promotes Adx detachment from AdR upon reduction. Here, we characterized the conformational dynamics of unbound Adx in the oxidized and reduced forms using 2-20 ns long molecular dynamics simulations. The most noticeable difference between both forms is the enhanced flexibility of the loop (47-51) surrounding the iron-sulfur cluster in the reduced form. Together with several structural displacements at the binding interface, this increased flexibility may be the key factor promoting unbinding of reduced Adx from AdR. This points to an intrinsic property of reduced Adx that drives dissociation.     

Molecular dynamics simulation by atomic mass weighting

A molecular dynamics-based simulation method in which atomic masses are weighted is described. Results from this method showed that the capability for conformation search in molecular dynamics simulation of a short peptide (FMRF-amide) is significantly increased by mass weighting.     

Molecular dynamics simulation of drug uptake by polymer

Drug uptake by polymer was modeled using a molecular dynamics (MD) simulation technique. Three drugs—doxorubicin (water soluble), silymarin (sparingly water soluble) and gliclazide (water insoluble)—and six polymers with varied functional groups—alginic acid, sodium alginate, chitosan, Gantrez AN119 (methyl-vinyl–ether-co-malic acid based), Eudragit L100 and Eudragit RSPO (both acrylic acid based)—were selected for the study. The structures were modeled and minimized using molecular mechanics force field (MM+). MD simulation (Gromacs-forcefield, 300 ps, 300 K) of the drug in the vicinity of the polymer molecule in the presence of water molecules was performed, and the interaction energy (IE) between them was calculated. This energy was evaluated with respect to electric-dipole, van der Waals and hydrogen bond forces. A good linear correlation was observed between IE and our own previous data on drug uptake^* [R ² = 0.65, R_adj² = 0.65,R_pre² = 0.56, {hbox{R}}_{rm{adj}}^2 = 0.65,{hbox{R}}_{rm{pre}}^2 = 0.56, and a F ratio of 30.25, P < 0.001; Devarajan et al. (2005) J Biomed Nanotechnol 1:1–9]. Maximum drug uptake by the polymeric nanoparticles (NP) was achieved in water as the solvent environment. Hydrophilic interaction between NP and water was inversely correlated with drug uptake. The MD simulation method provides a reasonable approximation of drug uptake that will be useful in developing polymer-based drug delivery systems.     

Molecular dynamics simulation of transmembrane polypeptide orientational fluctuations

The orientation and motion of a model lysine-terminated transmembrane polypeptide were investigated by molecular dynamics simulation. Recent 2H NMR studies of synthetic polypeptides with deuterated alanine side chains suggest that such transmembrane polypeptides undergo fast, axially symmetric reorientation about the bilayer normal but have a preferred average azimuthal orientation about the helix axis. In this work, interactions that might contribute to this behavior were investigated in a simulated system consisting of 64 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and one alpha-helical polypeptide with the sequence acetyl-KK-(LA)11-KK-amide. In one simulation, initiated with the peptide oriented along the bilayer normal, the system was allowed to evolve for 8.5 ns at 1 atm of pressure and a temperature of 55 degrees C. A second simulation was initiated with the peptide orientation chosen to match a set of experimentally observed alanine methyl deuteron quadrupole splittings and allowed to proceed for 10 ns. Simulated alanine methyl group orientations were found to be inequivalent, a result that is consistent with 2H NMR observations of specifically labeled polypeptides in POPC bilayers. Helix tilt varied substantially over the durations of both simulations. In the first simulation, the peptide tended toward an orientation about the helix axis similar to that suggested by experiment. In the second simulation, orientation about the helix axis tended to return to this value after an excursion. These results provide some insight into how interactions at the bilayer surface can constrain reorientation about the helix axis while accommodating large changes in helix tilt.     

Molecular dynamics simulation of sucrose- and trehalose-coated carboxy-myoglobin

We performed a room temperature molecular dynamics (MD) simulation on a system containing 1 carboxy-myoglobin (MbCO) molecule in a sucrose-water matrix of identical composition (89% [sucrose/(sucrose + water)] w/w) as for a previous trehalose-water-MbCO simulation (Cottone et al., Biophys J 2001;80:931-938). Results show that, as for trehalose, the amplitude of protein atomic mean-square fluctuations, on the nanosecond timescale, is reduced with respect to aqueous solutions also in sucrose. A detailed comparison as a function of residue number evidences mobility differences along the protein backbone, which can be related to a different efficacy in bioprotection. Different heme pocket structures are observed in the 2 systems. The joint distribution of the magnitude of the electric field at the CO oxygen atom and of the angle between the field and the CO unit vector shows a secondary maximum in sucrose, absent in trehalose. This can explain the CO stretching band profile (A substates distribution) differences evidenced by infrared spectroscopy in sucrose- and trehalose-coated MbCO (Giuffrida et al., J Phys Chem B 2004;108:15415-15421), and in particular the appearance of a further substate in sucrose. Analysis of hydrogen bonds at the protein-solvent interface shows that the fraction of water molecules shared between the protein and the sugar is lower in sucrose than in trehalose, in spite of a larger number of water molecules bound to the protein in the former system, thus indicating a lower protein-matrix coupling, as recently observed by Fourier transform infrared (FTIR) experiments (Giuffrida et al., J Phys Chem B 2004;108:15415-15421).     

Molecular dynamics simulation of interactions in glycolytic enzymes

Two glycolytic enzymes, phosphoglycerate mutase (PGM) and enolase from Saccharomyces cerevisiae, have been chosen to detect complex formation and possible channeling, using molecular dynamics simulation. The enzymes were separated by 10 angstroms distance and placed in a water-filled box of size 173 x 173 x 173 angstroms. Three different orientations have been investigated. The two initial 3-phosphoglycerate substrate molecules near the active centers of the initial structure of PGM have been replaced with final product (2-phosphoglycerate) molecules, and 150 mM NaCl together with three Mg2+ ions have been added to the system to observe post-catalytic activity under near-physiological conditions. Analysis of interaction energies and conformation changes for 3 nsec simulation indicates that PGM and enolase do show binding affinity between their near active regions, which is necessary for channeling to occur. Interaction of the C-terminal residues Ala239 and Val240 of PGM (which partially "cap" the 2-phosphoglycerate) with enolase also favors the existence of channeling.     

Molecular dynamics simulation of class 3 aldehyde dehydrogenase

Molecular dynamics (MD) simulation of the rat class 3 aldehyde dehydrogenase (ALDH) with nicotinamide dinucleotide (NAD) cofactors and explicit water molecules are reported. Our results demonstrate that MD simulation using the latest methodologies can maintain the crystal structure of the enzyme, as well as closely reproduce the short timescale dynamics of the enzyme. Furthermore, the examination of the distance between the nucleophilic Cys-243 and the NAD cofactor reveal important fluctuations that could be linked to ALDH catalysis. Finally, our quantum mechanical model of benzaldehyde in the active site of ALDH demonstrates that the enzyme requires only minor conformational changes to be poised for nucleophilic attack on the substrate.     

Molecular dynamics simulation of DPPC bilayer in DMSO

We performed molecular dynamics simulations on dipalmitoylphosphatidylcholine (DPPC)/dimethylsulfoxide (DMSO) system that has the same lipid:solvent weight ratio as in our previous simulation done on DPPC/water. We did not observe a large change in the size of DPPC membrane when the solvent was changed from water to DMSO. Also, we did not observe that a large number of DMSO molecules is permeating into the membrane, as it was suggested to explain the observed change in the bilayer repeat period. We found that the surface potential reverses its sign when water is replaced by DMSO. Based on the results from our simulations, we propose that the repulsion force acting between membranes is reduced when DMSO is added to solvent water and therefore membrane surfaces approach closer to each other and the extra solvent is removed into excess solution.     

Molecular dynamics simulation studies of lipid bilayer systems

The main structural element of biological membranes is a liquid-crystalline lipid bilayer. Other constituents, i.e. proteins, sterols and peptides, either intercalate into or loosely attach to the bilayer. We applied a molecular dynamics simulation method to study membrane systems at various levels of compositional complexity. The studies were started from simple lipid bilayers containing a single type phosphatidylcholine (PC) and water molecules (PC bilayers). As a next step, cholesterol (Chol) molecules were introduced to the PC bilayers (PC-Chol bilayers). These studies provided detailed information about the structure and dynamics of the membrane/water interface and the hydrocarbon chain region in bilayers built of various types of PCs and Chol. This enabled studies of membrane systems of higher complexity. They included the investigation of an integral membrane protein in its natural environment of a PC bilayer, and the antibacterial activity of magainin-2. The latter study required the construction of a model bacterial membrane which consisted of two types of phospholipids and counter ions. Whenever published experimental data were available, the results of the simulations were compared with them.