Molecular dynamics simulation shows large volume fluctuations of proteins

In this paper we present a new approach to study the volume fluctuations of proteins. From a 1 ns molecular dynamics simulation, the volume fluctuation of human lysozyme has been calculated. We used two different ways for the calculation. In the first one, the volume fluctuation is extracted directly from the trajectory. For the second one, a newly developed formalism based on principal component analysis is used. The r.m.s. volume fluctuations obtained from the two analyses agree well with each other. The isothermal intrinsic compressibility was found to be larger than the one reported by experiment. The difference is discussed and suggested to exist in the assumed uncertainty of the compressibility of hydrated water to deduce the isothermal intrinsic compressibility from the experimental value. Spectral analysis shows that low-frequency dynamics dominate the total volume fluctuation. The same aspect is found in the study using principal component analysis. This low-frequency region is related to large and slow motions of proteins. Therefore a long time dynamics simulation is necessary to describe the volume fluctuations of proteins.     

Molecular dynamics simulation of the transmembrane subunit of BtuCD in the lipid bilayer

Based on the crystal structure of the vitamin B12 transporter protein of Escherichia coli(BtuCD) a system consisting of the BtuCD transmembrane domain(BtuC) and the palmitoyloleoyl phosphatidylcholine(POPC) lipid bilayer was constructed in silica,and a more-than-57-nanosecond molecular dynamics(MD) simulation was performed on it to reveal the intrinsic functional motions of BtuC.The results showed that a stable protein-lipid bilayer was obtained and the POPC lipid bilayer was able to adjust its thickness to...     

Molecular dynamics generation of nonarbitrary membrane models reveals lipid orientational correlations

This report addresses the following problems associated with the generation of computer models of phospholipid bilayer membranes using molecular dynamics simulations: arbitrary initial structures and short equilibration periods, an Ewald-induced strong coupling of phospholipids, uncertainty regarding which value should be used for surface tension to alleviate the problem of the small size of the membrane, and simultaneous realization of both order parameters and the surface area. We generated a computer model of the liquid-crystalline L-alpha-dimyristoylphosphatidylcholine (DMPC) bilayer, starting from a configuration based on a crystal structure (rather than from an arbitrary structure). To break the crystalline structure, a 20-ps high-temperature pulse of 510 K (but not 450 or 480 K) was effective. The system finally obtained is an all-atom model, with Ewald summation to evaluate Coulombic interactions and a constant surface tension of 35 dynes/cm/water-membrane interface, equilibrated for 12 ns (over 50 ns total calculation time), which reproduces all of the experimentally observed parameters examined in this work. Furthermore, this model shows the presence of significant orientational correlations between neighboring alkyl chains and between shoulder vectors (which show the orientations of the lipids about their long axes) of neighboring DMPCs.     

Molecular dynamics simulation of SRP GTPases: Towards an understanding of the complex formation from equilibrium fluctuations

Signal recognition particle (SRP) and its receptor (SR) play essential role in the SRP‐dependent protein targeting pathway. They interact with one another to precisely regulate the targeting reaction. The mechanism of this interaction consists of at least two discrete conformational states: complex formation and GTPase activation. Although structural studies have provided valuable insights into the understanding of the SRP‐SR interaction, it still remains unclear that how SRP and SR GTPases use their intrinsic conformational flexibilities to exert multiple allosteric regulations on this interaction process. Here, we use computational simulations to present the dynamic behavior of the SRP GTPases at an atomic level to gain further understanding of SRP‐SR interaction. We show that: (i) equilibrium conformational fluctuations contain a cooperative inter‐ and intradomain structural rearrangements that are functionally relevant to complex formation, (ii) a series of residues in different domains are identified to correlate with each other during conformational rearrangements, and (iii) α3 and α4 helices at domain interface actively rearrange their relative conformation to function as a bridge between the N domain and the core region of the G domain. These results, in addition to structural studies, would harness our understanding of the molecular mechanism for SRP and SR interaction. Proteins 2010. © 2010 Wiley‐Liss, Inc.     

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.     

Molecular dynamics simulations of isolated transmembrane helices of potassium channels

In the middle of the S6 helix in voltage-gated potassium channels there is a highly conserved Pro-Val-Pro motif, while the equivalent M2 helix of inward rectifier potassium channels contains a conserved glycine residue in a comparable position. The structural implications of these conserved motifs are of interest given the evidence that S6 and M2 are components of the lining of their respective pores. Multiple sequence alignment and TM helix prediction methods were used to define consensus regions for S6 and M2. Ensembles of 50 structures for each helix were generated by simulated annealing and restrained molecular dynamics. Time-dependent fluctuations of S6 and M2 were investigated by long time scale molecular dynamics simulations on representative members of each ensemble carried out in vacuo in the presence and absence of a hydrophobic potential that mimics a lipid bilayer. The results are discussed in terms of the structural basis of the kink in S6 and M2 and of a putative functional role for flexible helices as “molecular swivels.” © 1996 John Wiley & Sons, Inc.     

Lipid bilayer polypeptide interactions studied by molecular dynamics simulation

A model membrane with a polypeptide alpha-helix inserted has been simulated by molecular dynamics at a temperature well above the gel/liquid crystalline phase transition temperature. Order parameters of the lipids and other equilibrium and dynamic quantities have been calculated. Three systems, polyglycine constrained into an alphahelical configuration, glycophorin with similarly conformationally constrained backbone and finally glycophorin free to change its backbone conformation, have been studied. In all cases there was an ordering of the chains close to the helix. This effect was, however, much smaller for glycophorin with its rather bulky side chains than for polyglycine. The dynamics of the lipids were affected by the neighbouring helix, not drastically however. Lateral diffusion and reorientational time correlations of lipids close to the helix were slower than for the bulk ones, but not more than two or three times. Thus, we did not find any evidence of bound or frozen boundary lipids.     

Molecular dynamics study of ion transport in transmembrane protein channels

Ion transport through biological membranes often takes place via pore-like protein channels. The elementary process of this transport can be described as a motion of the ion in a quasi-periodic multi-well potential. In this study molecular dynamics simulations of ion transport in a model channel were performed in order to test the validity of reaction-rate theory for this process. The channel is modelled as a hexagonal helix of infinite length, and the ligand groups interacting with the ion are represented by dipoles lining the central hole of the channel. The dipoles interact electrostatically with each other and are allowed to oscillate around an equilibrium orientation. The coupled equations of motion for the ion and the dipoles were solved simultaneously with the aid of a numerical integration procedure. From the calculated ion trajectories it is seen that, particularly at low temperatures, the ion oscillates back and forth in the trapping site many times before it leaves the site and jumps over the barrier. The observed oscillation frequency was found to be virtually temperature-independent (nu 0 approximately equal to 2 X 10(12) s-1) so that the strong increase of transport rate with temperature results almost exclusively from the Arrhenius-type exponential dependence of jump probability w on 1/T. At higher temperatures simultaneous jumps over several barriers occasionally occur. Although the exponential form of w(T) was in agreement with the predictions of rate theory, the activation energy Ea as determined from w(T) was different from the barrier height which was calculated from the static potential of the ion in the channel; the actual transport rate was 1 X 10(3) times higher than the rate predicted from the calculated barrier height. This observation was interpreted by the notion that ion transport in the channel is strongly influenced by thermal fluctuations in the conformation of the ligand system which in turn give rise to fluctuations of barrier height.     

Mass-weighted molecular dynamics simulation and conformational analysis of polypeptide.

Atomic motions in protein molecules have been studied by molecular dynamics (MD) simulations; dynamics simulation methods have also been employed in conformational studies of polypeptide molecules. It was found that when atomic masses are weighted, the molecular dynamics method can significantly increase the sampling of dihedral conformation space in such studies, compared to a conventional MD simulation of the same total simulation time length. Herein the theoretical study of molecular conformation sampling by the molecular dynamics-based simulation method in which atomic masses are weighted is reported in detail; moreover, a numerical scheme for analyzing the extensive conformational sampling in the simulation of a tetrapeptide amide molecule is presented. From numerical analyses of the mass-weighted molecular dynamics trajectories of backbone dihedral angles, low-resolution structures covering the entire backbone dihedral conformation space of the molecule were determined, and the distribution of rotationally stable conformations in this space were analyzed quantitatively. The theoretical analyses based on the computer simulation and numerical analytical methods suggest that distinctive regimes in the conformational space of the peptide molecule can be identified.     

Molecular dynamics of bending fluctuations in the protein secondary structures

A comparative study of the dynamics of protein secondary structure elements by the example of alpha-helices of myoglobin, barnase, polylysine, and polyglycine and beta-layers of barnase and GFP was carried out by the methods of molecular dynamics. The effective Young's moduli of both free secondary structure elements and those built in the protein globule were determined. A heterogeneity of the elastic properties of the secondary structure elements was found. The melting of myoglobin alpha-helix in a virtual viscous medium was studied.     

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 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 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 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.