Molecular dynamics simulation of a synthetic ion channel.

A molecular dynamics simulation has been performed on a synthetic membrane-spanning ion channel, consisting of four alpha-helical peptides, each of which is composed of the amino acids leucine (L) and serine (S), with the sequence Ac-(LSLLLSL)3-CONH2. This four-helix bundle has been shown experimentally to act as a proton-conducting channel in a membrane environment. In the present simulation, the channel was initially assembled as a parallel bundle in the octane portion of a phase-separated water/octane system, which provided a membrane-mimetic environment. An explicit reversible multiple-time-step integrator was used to generate a dynamical trajectory, a few nanoseconds in duration for this composite system on a parallel computer, under ambient conditions. After more than 1 ns, the four helices were found to adopt an associated dimer state with twofold symmetry, which evolved into a coiled-coil tetrameric structure with a left-handed twist. In the coiled-coil state, the polar serine side chains interact to form a layered structure with the core of the bundle filled with H2O. The dipoles of these H2O molecules tended to align opposite the net dipole of the peptide bundle. The calculated dipole relaxation function of the pore H2O molecules exhibits two reorientation times. One is approximately 3.2 ps, and the other is approximately 100 times longer. The diffusion coefficient of the pore H2O is about one-third of the bulk H2O value. The total dipole moment and the inertia tensor of the peptide bundle have been calculated and reveal slow (300 ps) collective oscillatory motions. Our results, which are based on a simple united atom force-field model, suggest that the function of this synthetic ion channel is likely inextricably coupled to its dynamical behavior.     

Molecular dynamics simulation of melittin in a dimyristoylphosphatidylcholine bilayer membrane.

Molecular dynamics trajectories of melittin in an explicit dimyristoyl phosphatidylcholine (DMPC) bilayer are generated to study the details of lipid-protein interactions at the microscopic level. Melittin, a small amphipathic peptide found in bee venom, is known to have a pronounced effect on the lysis of membranes. The peptide is initially set parallel to the membrane-solution interfacial region in an alpha-helical conformation with unprotonated N-terminus. Solid-state nuclear magnetic resonance (NMR) and polarized attenuated total internal reflectance Fourier transform infrared (PATIR-FTIR) properties of melittin are calculated from the trajectory to characterize the orientation of the peptide relative to the bilayer. The residue Lys7 located in the hydrophobic moiety of the helix and residues Lys23, Arg24, Gln25, and Gln26 at the C-terminus hydrophilic form hydrogen bonds with water molecules and with the ester carbonyl groups of the lipids, suggesting their important contribution to the stability of the helix in the bilayer. Lipid acyl chains are closely packed around melittin, contributing to the stable association with the membrane. Calculated density profiles and order parameters of the lipid acyl chains averaged over the molecular dynamics trajectory indicate that melittin has effects on both layers of the membrane. The presence of melittin in the upper layer causes a local thinning of the bilayer that favors the penetration of water through the lower layer. The energetic factors involved in the association of melittin at the membrane surface are characterized using an implicit mean-field model in which the membrane and the surrounding solvent are represented as structureless continuum dielectric material. The results obtained by solving the Poisson-Bolztmann equation numerically are in qualitative agreement with the detailed dynamics. The influence of the protonation state of the N-terminus of melittin is examined. After 600 ps, the N-terminus of melittin is protonated and the trajectory is continued for 400 ps, which leads to an important penetration of water molecules into the bilayer. These observations provide insights into how melittin interacts with membranes and the mechanism by which it enhances their lysis.     

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 study of the static and dynamic properties of a model colloidal suspension with explicit solvent

Molecular dynamics simulation was used to study a colloidal suspension with explicit solvent to determine how inclusion of the solvent affects the structure and dynamics of the system. The solute was modelled as a hard-core particle enclosed in a Weeks–Chandler–Andersen (WCA) potential shell, while the solvent was modelled as a simple WCA fluid. We found that when the solute–solvent interaction included a hard core equal to half of the solute hard-core diameter, large depletion effects arose, leading to an effective attraction and large deviations from hard-sphere structure for the colloidal component. It was found that these effects could be eliminated by reducing the hard-core distance parameter in the solute–solvent interaction, thus allowing the solvent to penetrate closer to the colloidal particles. Three different values for the solute–solvent hard-core parameter were systematically studied by comparing the static structure factor and radial distribution function to the predictions of the Percus–Yevick theory for hard spheres. When the optimal value of the solute–solvent hard-core interaction parameter was found, this model was then used to study the dynamical behaviour of the colloidal suspension. This was done by first measuring the velocity autocorrelation function (VACF) over a large range of packing fractions. We found that this model predicted the sign of the long-time tail in the VACF in agreement with experimental values, something that single component hard-sphere systems have failed to do. The intermediate scattering functions at low wavevector were briefly studied to determine their behaviour in a dilute system. It was found that they could be modelled using a simple diffusion equation with a wavevector independent diffusion coefficient, making this model an excellent analogue of experimentally studied hard-sphere colloids.     

Molecular dynamics simulation of a high-affinity antibody-protein complex

One nanosecond molecular dynamic (MD) simulation of anti-hen egg white lysozyme (HEL) antibody HyHEL63 (HH63) complexed with HEL reveals rigid and flexible regions of the HH63 binding site. Fifty conformations, extracted from the MD trajectory at regular time intervals were superimposed on HH63-HEL X-ray crystal structure, and the root mean squared deviations (RMSDs) and deviations in Calpha atom positions between the X-ray structure and the MD conformer were measured. Residue positions showing the large deviations in both light chain and heavy chain of the antibody were same in all the MD conformers. The residue positions showing smallest deviations were same for all the conformers in the case of light chain, whereas relatively variable in the heavy chain. Positions of large and small deviations fell in the complementarity determining regions (CDRs), for both heavy and light chains. The larger deviations were in CDR-2 of light and CDR-1 of heavy chain. Smaller deviations were in CDR-3 of light and CDR-2 and CDR-3 of heavy chains. The large and small deviating regions highlight flexible and rigid regions of HH63 binding site and suggest a mosaic binding mechanism, including both "induced fit" and preconfigured "lock-and-key" type of binding. Combined "induced fit" and "lock-and-key" binding would be a better definition for the formation of large complexes, which bury larger surface area on binding, as in the case of antibody-HEL complex. We further show that flexible regions, comprising mostly charged and polar residues, form intermolecular interactions with HEL, whereas rigid regions do not. Electrostatic complementarity between HH63 and HEL also imply optimized binding affinity. Flexible and rigid regions of a high-affinity antibody are selected during the affinity maturation of the antibody and have specific functional significance. The functional importance of local inherently flexible regions is to establish intermolecular contacts or they play a key role in molecular recognition, whereas local rigid regions provide the structural framework.     

Molecular dynamics simulations of DNA and a protein-DNA complex including solvent

The results of a recent nanosecond (ns) molecular dynamics (MD) simulation of the d(CGCGAATTCGCG) double helix in water and a 100 ps MD study of the repressor-operator complex are described. The DNA simulations are analyzed in terms of the structural dynamics, fluctuations in the groove width and bending of the helical axis. The results indicate that the ns dynamical trajectory progresses through a series of three substates of B form DNA, with lifetimes of the order of hundreds of picoseconds (ps). An incipient dynamical equilibrium is evident. A comparison of the calculated axis bending with that observed in corresponding crystal structure data is presented. Simulation of the DNA in complex with the protein and that of the free DNA in solution, starting from the crystal conformation, reveal the dynamical changes that occur on complex formation.     

Molecular dynamics simulation of Pf1 coat protein.

The results of molecular dynamics simulations of Pf1 coat protein are described and compared to experimental NMR data on both the membrane bound and structural forms of this viral coat protein. Molecular dynamics simulations of the 46 residue coat protein and related model sequences were performed according to a simple protocol. The simulations were initiated with the polypeptides in a completely uniform alpha helical conformation in a dielectric continuum (epsilon = 2) and the motions of individual residues were followed as a function of time by monitoring the angular fluctuations of amide NH bond vectors. The simulations of Pf1 coat protein were able to identify the same mobile and structured segments found in experimental NMR studies of the membrane bound form of the protein (Shon, K.-J., Y. Kim, L. A. Colnago, and S. J. Opella. 1991. Science (Wash. DC). 252:1303-1305). Significantly, in addition to mobile amino and carboxyl terminal regions, a mobile internal loop was found that connects the rigid hydrophobic and amphipathic helices in the protein. NMR experiments show that this mobile loop is present in both the viral and membrane bound forms of the protein and that it plays a role in viral assembly (Nambudripad, R., W. Stark, S. J. Opella, and L. Makowski. 1991. Science (Wash. DC) 252:1305-1308). The results of simulations of several alanine based 46 residue polypeptides with some of the charged residues present in the Pf1 coat protein sequence suggest that interactions between the Asp 14 and Asp 18 sidechains and the peptide backbone are responsible for the formation of the mobile loop.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular dynamics simulation of carboxy-myoglobin embedded in a trehalose-water matrix

We report on a molecular dynamics (MD) simulation of carboxy-myoglobin (MbCO) embedded in a water-trehalose system. The mean square fluctuations of protein atoms, calculated at different temperatures in the 100-300 K range, are compared with those from a previous MD simulation on an H2O-solvated MbCO and with experimental data from M?ssbauer spectroscopy and incoherent elastic neutron scattering on trehalose-coated MbCO. The results show that, for almost all the atomic classes, the amplitude of the nonharmonic motions stemming from the interconversion among the protein's conformational substates is reduced with respect to the H2O-solvated system, and their onset is shifted toward higher temperature. Moreover, our simulation shows that, at 300 K, the heme performs confined diffusive motions as a whole, leaving the underlying harmonic vibrations unaltered.     

Molecular dynamics simulation of solvated azurin: correlation between surface solvent accessibility and water residence times

A system containing the globular protein azurin and 3,658 water molecules has been simulated to investigate the influence on water dynamics exerted by a protein surface. Evaluation of water mean residence time for elements having different secondary structure did not show any correlation. Identically, comparison of solvent residence time for atoms having different charge and polarity did not show any clear trend. The main factor influencing water residence time in proximity to a specific site was found to be its solvent accessibility. In detail for atoms belonging to lateral chains and having solvent-accessible surface lower than approximately 16 A(2)a relation is found for which charged and polar atoms are surrounded by water molecules characterized by residence times longer than the non polar ones. The involvement of the low accessible protein atom in an intraprotein hydrogen bond further modulates the length of the water residence time. On the other hand for surfaces having high solvent accessibility, all atoms, independently of their character, are surrounded by water molecules which rapidly exchange with the bulk solvent. Proteins 2000;39:56-67.     

Molecular dynamics simulations of folding processes of a beta-hairpin in an implicit solvent

Computer simulations of beta-hairpin folding are relatively difficult, especially those based on the explicit water model. This greatly limits the complete analysis and understanding of their folding mechanisms. In this paper, we use the generalized Born/solvent accessible implicit solvent model to simulate the folding processes of a nine-residue beta-hairpin. We find that the beta-hairpin can fold into its native structure very easily, even using the traditional molecular dynamics method. This allows us to extract 21 complete folding events and investigate the folding process sufficiently. Our results show that there exist four most stable states on the free energy landscape of the short peptide, one native state and three intermediates. We find that two of the non-native stable states have almost the same potential energy as the native state but with lower entropy. This suggests that the native state can be stabilized entropically. Furthermore, we find that the folding processes of this peptide have common features: to fold into its native state, the peptide undergoes a continuous collapsing-extending-recollapsing process to adjust the positions of the side chains in order to form the native middle inter-strand hydrogen bonds. The formations of these bonds are the key step of the folding process. Once these bonds are formed, the peptide can fold into the native state quickly.     

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 studies of a DNA-binding protein: 2. An evaluation of implicit and explicit solvent models for the molecular dynamics simulation of the Escherichia coli trp repressor.

Although aqueous simulations with periodic boundary conditions more accurately describe protein dynamics than in vacuo simulations, these are computationally intensive for most proteins. Trp repressor dynamic simulations with a small water shell surrounding the starting model yield protein trajectories that are markedly improved over gas phase, yet computationally efficient. Explicit water in molecular dynamics simulations maintains surface exposure of protein hydrophilic atoms and burial of hydrophobic atoms by opposing the otherwise asymmetric protein-protein forces. This properly orients protein surface side chains, reduces protein fluctuations, and lowers the overall root mean square deviation from the crystal structure. For simulations with crystallographic waters only, a linear or sigmoidal distance-dependent dielectric yields a much better trajectory than does a constant dielectric model. As more water is added to the starting model, the differences between using distance-dependent and constant dielectric models becomes smaller, although the linear distance-dependent dielectric yields an average structure closer to the crystal structure than does a constant dielectric model. Multiplicative constants greater than one, for the linear distance-dependent dielectric simulations, produced trajectories that are progressively worse in describing trp repressor dynamics. Simulations of bovine pancreatic trypsin were used to ensure that the trp repressor results were not protein dependent and to explore the effect of the nonbonded cutoff on the distance-dependent and constant dielectric simulation models. The nonbonded cutoff markedly affected the constant but not distance-dependent dielectric bovine pancreatic trypsin inhibitor simulations. As with trp repressor, the distance-dependent dielectric model with a shell of water surrounding the protein produced a trajectory in better agreement with the crystal structure than a constant dielectric model, and the physical properties of the trajectory average structure, both with and without a nonbonded cutoff, were comparable.     

Molecular dynamics simulation of a dipalmitoylphosphatidylcholine bilayer with NaCl

Molecular dynamics simulations are performed on two hydrated dipalmitoylphosphatidylcholine bilayer systems: one with pure water and one with added NaCl. Due to the rugged nature of the membrane/electrolyte interface, ion binding to the membrane surface is characterized by the loss of ion hydration. Using this structural characterization, binding of Na(+) and Cl(-) ions to the membrane is observed, although the binding of Cl(-) is seen to be slightly weaker than that of Na(+). Dehydration is seen to occur to a different extent for each type of ion. In addition, the excess binding of Na(+) gives rise to a net positive surface charge density just outside the bilayer. The positive density produces a positive electrostatic potential in this region, whereas the system without salt shows an electrostatic potential of zero.     

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.     

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.     

Anti-insulin antibody structure and conformation. II. Molecular dynamics with explicit solvent.

Molecular dynamics at 300 K was used as a conformation searching tool to analyze a knowledge-based structure prediction of an anti-insulin antibody. Solvation effects were modeled by packing water molecules around the antigen binding loops. Some loops underwent backbone and side-chain conformational changes during the 95-ps equilibration, and most of these new, lower potential energy conformations were stable during the subsequent 200-ps simulation. Alterations to the model include changes in the intraloop, main-chain hydrogen bonding network of loop H3, and adjustments of Tyr and Lys side chains of H3 induced by hydrogen bonding to water molecules. The structures observed during molecular dynamics support the conclusion of the previous paper that hydrogen bonding will play the dominant role in antibody-insulin recognition. Determination of the structure of the antibody by x-ray crystallography is currently being pursued to provide an experimental test of these results. The simulation appears to improve the model, but longer simulations at higher temperatures should be performed.     

Molecular dynamics simulation of cation motion in water-filled gramicidinlike pores.

A model calculation is carried out to study the potential energy profile of a sodium ion with several water molecules inside a simplified model of the gramicidin ion channel. The sodium ion is treated as a Lennard-Jones sphere with a point charge at its center. The Barnes polarizable water model is used to mimic the water molecules. A polarizable and deformable gramicidinlike channel is constructed based on the model obtained by Koeppe and Kimura. Potential minima and saddle points are located and the static energy barriers are computed. The potential minima at the two mouths of the channel exhibit an aqueous solvation structure very different from that at any of the interior minima. These sites are approximately 23.6 and 24.4 A apart for binding of a sodium ion and a cesium ion, respectively. Ionic motion from these exterior sites to the first interior minimum requires substantial rearrangement of the waters of solvation; this rearrangement may be the hydration/dehydration step in ionic permeation through the channel. Based on these results, a mechanism by which the sodium ion moves from the exterior binding site to the interior of the channel is proposed. Our model channel accommodates about eight water molecules and the transport of the ion and water within the channel is found to be single file. Results of less extensive calculations for Cs+ and Li+ ions in a channel with or without water are also reported.     

Molecular dynamics simulation of solvated protein at high pressure.

We have completed a molecular dynamics simulation of protein (bovine pancreatic trypsin inhibitor, BPTI) in solution at high pressure (10 kbar). The structural and energetic effects of the application of high pressure to solvated protein are analyzed by comparing the results of the high-pressure simulation with a corresponding simulation at low pressure. The volume of the simulation cell containing one protein molecule plus 2943 water molecules decreases by 24.7% at high pressure. This corresponds to a compressibility for the protein solution of beta = 1.8 x 10(-2) kbar-1. The compressibility of the protein is estimated to be about one-tenth that of bulk water, while the protein hydration layer water is found to have a greater compressibility as compared to the bulk, especially for water associated with hydrophobic groups. The radius of gyration of BPTI decreases by 2% and there is a one third decrease in the protein backbone atomic fluctuations at high pressure. We have analyzed pressure effects on the hydration energy of the protein. The total hydration energy is slightly (4%) more favorable at high pressure even though the surface accessibility of the protein has decreased by a corresponding amount. Large pressure-induced changes in the structure of the hydration shell are observed. Overall, the solvation shell waters appear more ordered at high pressure; the pressure-induced ordering is greatest for nonpolar surface groups. We do not observe evidence of pressure-induced unfolding of the protein over the 100-ps duration of the high-pressure simulation. This is consistent with the results of high-pressure optical experiments on BPTI.(ABSTRACT TRUNCATED AT 250 WORDS)