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Thermodynamic data are often used to calibrate or test atomic-level (AL) force fields for molecular dynamics (MD) simulations. In contrast, the majority of coarse-grained (CG) force fields do not rely extensively on thermodynamic quantities. Recently, a CG force field for lipids, hydrocarbons, ions, and water, [1] in which approximately four non-hydrogen atoms are mapped onto one interaction site, has been proposed and applied to study various aspects of lipid systems. To date, no extensive investigation of its capability to describe salvation thermodynamics has been undertaken. In the present study, a detailed picture of vaporization, solvation, and phase-partitioning thermodynamics for liquid hydrocarbons and water was obtained at CG and AL resolutions, in order to compare the two types of models and evaluate their ability to describe thermodynamic properties in the temperature range between 263 and 343 K. Both CG and AL models capture the experimental dependence of the thermodynamic properties on the temperature, albeit a systematically weaker dependence is found for the CG model. Moreover, deviations are found for solvation thermodynamics and for the corresponding enthalpy-entropy compensation for the CG model. Particularly water/oil repulsion seems to be overestimated. However, the results suggest that the thermodynamic properties considered should be reproducible by a CG model provided it is reparametrized on the basis of these liquid-phase properties.

Binary mixtures of two phosphatidylcholines of different chain lengths are simulated in the bilayer state. We find a phase transition between a liquid state and a gel state at all concentrations. This phase transition is characterized by the area per lipid headgroup, the order parameter, and a change in dynamics. At concentrations with a majority of the longer lipid, we find phase separation into a gel and a liquid state in a small temperature window. This leads to a strong dynamic heterogeneity. Experimental phase transition temperatures are reproduced semiquantitatively. We see a clear shift in the phase transition to higher temperatures with increasing concentration of the longer lipid.

Extensive molecular dynamics (MD) simulations of binary systems of phospholipids and bile salts, a model for human bile, have been performed. Recent progress in hardware and software development allows simulation of the spontaneous aggregation of the constituents into small mixed micelles, in agreement with experimental observations. The MD simulations reveal the structure of these micelles at atomic detail. The phospholipids are packed radially with their headgroups at the surface and the hydrophobic tails pointing toward the micellar center. The bile salts act as wedges between the phospholipid headgroups, with their hydrophilic sides exposed to the aqueous environment. The structure of the micelles strongly resembles the previously proposed radial shell model. Simulations including small fractions of cholesterol reveal how cholesterol is solubilized inside these mixed micelles without changing their overall structure.

Haloalkane dehalogenase (DhlA) was used as a model protein to explore the possibility to use molecular dynamics (MD) simulations as a tool to identify flexible regions in proteins that can serve as a target for stability enhancement by introduction of a disulfide bond. DhlA consists of two domains: an alpha/beta-hydrolase fold main domain and a cap domain composed of five alpha-helices. MD simulations of DhlA showed high mobility in a helix-loop-helix region in the cap domain, involving residues 184-211. A disulfide cross-link was engineered between residue 201 of this flexible region and residue 16 of the main domain. The mutant enzyme showed substantial changes in both thermal and urea denaturation. The oxidized form of the mutant enzyme showed an increase of the apparent transition temperature from 47.5 to 52.5 degrees C, whereas the T(m,app) of the reduced mutant decreased by more than 8 degrees C compared to the wild-type enzyme. Urea denaturation results showed a similar trend. Measurement of the kinetic stability showed that the introduction of the disulfide bond caused a decrease in activation free energy of unfolding of 0.43 kcal mol(-1) compared to the wild-type enzyme and also indicated that the helix-loop-helix region was involved early in the unfolding process. The results show that MD simulations are capable of identifying mobile protein domains that can successfully be used as a target for stability enhancement by the introduction of a disulfide cross-link.

We present an algorithm to compute the number of solutions of the (constrained) number partitioning problem. A concrete implementation of the algorithm on an Ising-type quantum computer is given., Comment: 5 pages, 1 figure, see also http://rugth30.phys.rug.nl/compphys/qce.htm

In this article we show how the quasi-Gaussian entropy (QGE) theory can be used to treat systems of polyatomic flexible molecules, where the usual semirigid description is not always appropriate. We describe a completely general derivation of the QGE theory which does not make use of any semirigid approximation, and therefore it is very suited for large and flexible molecules. Using molecular dynamics simulations of flexible molecules in vacuo, we investigated the ability of the theory to describe intramolecular energy fluctuations and conformational equilibria of purely classical molecules in the ideal gas condition. Results show that the gamma state level of the theory and its generalization for treating conformational equilibria (multi-gamma state model) provide excellent theoretical models when applied to three polyatomic molecules of increasing conformational freedom.

This paper presents the first atomistic simulation of a cubic membrane phase. Using the molecular dynamics simulation technique both the global and the local organization of glycerolmonoolein molecules inside the diamond cubic phase are studied. Multinanosecond simulations reveal that the center of the cubic bilayer remains close to the infinite periodic minimal surface that describes the diamond geometry. We further show that the equilibrium structure of the surfactant molecules inside the cubic phase is very similar to their structure inside a simulated lamellar bilayer. The small differences arise from the packing constraints of the surfactants within the cubic phase which has an area per surfactant that increases toward the bilayer center.

This paper reviews a general method to characterize the morphology of two- and three-dimensional patterns in terms of geometrical and topological descriptors. Based on concepts of integral geometry, it involves the calculation of the Minkowski functionals of black-and-white images representing the patterns. The result of this approach is an objective, numerical characterization of a given pattern. We briefly review the basic elements of morphological image processing, a technique to transform images to patterns that are amenable to further morphological image analysis. The image processing technique is applied to electron microscope images of nano-ceramic particles and metal-oxide precipitates. The emphasis of this review is on the practical aspects of the integral-geometry-based morphological image analysis but we discuss its mathematical foundations as well. Applications to simple lattice structures, triply periodic minimal surfaces, and the Klein bottle serve to illustrate the basic steps of the approach. More advanced applications include random point sets, percolation and complex structures found in block copolymers.

Geometrical patterns are encountered in many different fields of science and technology, including porous media, biology, polymer chemistry, metallography, geology and astronomy. 1),2) We characterize these patterns in terms of shape (geometry) and connectivity (topology) by means of morphological image analysis (MIA). This involves the calculation of the Minkowski functionals known from integral geometry. 3), 4) These functionals are related to familiar measures: In two (three) dimensions they correspond to the covered area, boundary length, and connectivity (volume, surface area, integral mean curvature and connectivity) of the pattern. For sufficiently smooth and regular objects some of these measures are related to quantities known from differential geometry. Integral geometry imposes no limitations on the properties of the patterns. Furthermore in integral geometry the calculation of the Minkowski functionals is relatively straightforward and requires little computational effort. 22) Given a set of patterns the first step in MIA is to compute the Minkowski functionals themselves. The second step is to analyze the behavior of the Minkowski functionals as a function of control parameters. This approach has proven to be instrumental to describe the morphology of porous media and complex fluids, the large-scale distribution of matter in the Universe, microemulsions, patterns in reaction diffusion systems, and spinodal decomposition kinetics. 5) In this paper we briefly discuss the underlying mathematics of the Minkowski functionals and the algorithm to compute them. We illustrate the application of MIA to three-dimensional (3D) patterns taken from polymer chemistry and to minimal surfaces.

We present the newest version of the GROningen MOlecular Simulation program package, GROMOS96. GROMOS96 has been developed for the dynamic modelling of (bio)molecules using the methods of molecular dynamics, stochastic dynamics, and energy minimization as well as the path-integral formalism. An overview of its functionality is given, highlighting methodology not present in the last major release, GROMOS87. The organization of the code is outlined, and reliability, testing, and efficiency issues involved in the design of this large (73 000 lines of FORTRAN77 code) and complex package are discussed. Finally, we present two applications illustrating new functionality: local elevation simulation and molecular dynamics in four spatial dimensions.

Mol. dynamics simulation studies on the folding of beta-peptides H-beta3-HVal-beta3-HAla-beta3-HLeu-(S,S)-beta3-HAla(alphaMe)-beta3-HVal-beta3-HAla-beta3-HLeu-OH and H-beta2-HVal-beta3-HAla-beta2-HLeu-beta3-HVal-beta2-HAla-beta3-HLeu-OH were carried out. Despite the small differences in sequence between the two peptides studied, the simulations correctly predict a left-handed 31-helical fold for the beta-heptapeptide and a right-handed helical fold for the beta-hexapeptide.

The implementation of cutinase from Fusarium solani pisi as a fat-stain removing ingredient in laundry washing is hampered by its unfolding in the presence of anionic surfactants. In this work we present molecular dynamics (MD) computer simulations on cutinase and analysis procedures to distinguish the movements related to its functional behavior (e.g., substrate binding) from those related to the unfolding of the enzyme. Two kinds of MD-simulations were performed: a simulation mimicking the thermal motion at room temperature, and several simulations in which unfolding is induced either by high temperature or by using a modified water-protein interaction potential. Essential dynamics analyses (A. Amadei et al., Proteins 17:412–425, 1993) on the simulations identify distinct regions in the molecular structure of cutinase in which the motions occur for function and initial unfolding. The unfolding in various simulations starts in a similar way, suggesting that mutations in the regions involved might stabilize the enzyme without affecting its functionality. Proteins 33:253–264, 1998. © 1998 Wiley-Liss, Inc.

Nuclear spin relaxation is a powerful method for studying molecular dynamics at atomic resolution. Recent methods development in biomolecular NMR spectroscopy has enabled detailed investigations of molecular dynamics that are critical for biological function, with prominent examples addressing allostery, enzyme catalysis, and protein folding. Dynamic processes with similar correlation times are often detected in multiple locations of the molecule, raising the question of whether the underlying motions are correlated (corresponding to concerted fluctuations involving many atoms distributed across extended regions of the molecule) or uncorrelated (corresponding to independent fluctuations involving few atoms in localized regions). Here, we have used 13 C α ( i - 1)/ 13 C α ( i ) differential multiple-quantum spin relaxation to provide direct evidence for correlated dynamics of consecutive amino acid residues in the protein sequence. By monitoring overlapping pairs of residues ( i - 1 and i , i and i + 1, etc.), we identified correlated motions that extend through continuous segments of the sequence. We detected significant correlated conformational transitions in the native state of the E140Q mutant of the calmodulin C-terminal domain. Previous work has shown that this domain exchanges between two major conformational states that resemble the functionally relevant open and closed states of the WT protein, with a mean correlation time of ≈20 μs. The present results reveal that an entire α-helix undergoes partial unraveling in a transient and cooperative manner.

Most of the fundamental biological tasks within living cells are performed by protein molecules. Although all natural proteins are built essentially from the same set of 20 amino acids, they exhibit a huge diversity of three-dimensional structure and an even greater range of function. ... Zie: Summary

The design of a transmembrane four-helix bundle is described. We start with an idealized four-helix bundle geometry, then use statistical information to build a plausible transmembrane bundle. Appropriate residues are chosen using database knowledge on the sequences of membrane helices and loops, then the packing of the bundle core is optimized, and favorable side chain rotamers from rotamer libraries are selected. Next, we use explicit physical knowledge from biomolecular simulation force fields and molecular dynamics simulations to test whether the designed structure is physically possible. These procedures test whether the designed protein will indeed be α-helical, well packed and stable over a time scale of several nanoseconds in a realistic lipid bilayer environment. We then test a modeling approach that does not include sophisticated database knowledge about proteins, but rather relies on applying our knowledge of the physics that governs protein motions. This independent validation of the design is based on simulated annealing and restrained molecular dynamics simulation in vacuo, comparable to procedures used to refine NMR and X-ray structures.

We study effects of the physical realization of quantum computers on their logical operation. Through simulation of physical models of quantum computer hardware, we analyze the difficulties that are encountered in programming physical realizations of quantum computers. Examples of logically identical implementations of the controlled-NOT operation and Grover's database search algorithm are used to demonstrate that the results of a quantum computation are unstable with respect to the physical realization of the quantum computer. We discuss the origin of these instabilities and discuss possibilities to overcome this, for practical purposes, fundamental limitation of quantum computers.

We discuss the impact of the physical implementation of a quantum computer on its computational efficiency, using computer simulations of physical models of quantum computer hardware. We address the computational efficiency of practical procedures to extract the results of a quantum computation from the wave function respresenting the final state of the quantum computer.

To understand the effect of the finite size of simulation cells on the equilibrium properties of bilayers, an extensive series of glycerolmonoolein bilayer molecular dynamics simulations in which the surface area and system size were systematically changed have been conducted. Systems ranging from 200 to 1800 lipids were simulated, covering length scales up to 20 nm. The dependence of the surface tension on the area per lipid is shown, although long simulation times were needed (up to 40 ns) to obtain reliable estimates. As the size of simulated patches increases, long wavelength undulatory modes appear with a concomitant increase in the area compressibility due to coupling of undulation modes to area fluctuations. Both the undulatory intensities and the peristaltic intensities of the bilayer fluctuations can be fitted in the long wavelength limit to continuum model predictions. The effect of system size on surface tension appears to depend on the stress conditions.

To evaluate the ability of molecular dynamics (MD) simulations using atomic force-fields to correctly predict stable folded conformations of a peptide in solution, we show results from MD simulations of the reversible folding of an octapeptide rich in alpha-aminoisobutyric acid (2-amino-2-methyl-propanoic acid, Aib) solvated in di-methyl-sulfoxide (DMSO). This solvent generally prevents the formation of secondary structure, whereas Aib-rich peptides show a high propensity to form secondary structural elements, in particular 3(10)- and alpha-helical structures. Aib is, moreover, achiral, so that Aib-rich peptides can form left- or right-handed helices depending on the overall composition of the peptide, the temperature, and the solvation conditions. This makes the system an interesting case to study the ensembles of peptide conformations as a function of temperature by MD simulation. Simulations involving the folding and unfolding of the peptide were performed starting from two initial structures, a right-handed alpha-helical structure and an extended structure, at three temperatures, 298 K, 340 K, and 380 K, and the results are compared with experimental nuclear magnetic resonance (NMR) data measured at 298 K and 340 K. The simulations generally reproduce the available experimental nuclear Overhauser effect (NOE) data, even when a wide range of conformations is sampled at each temperature. The importance of adequate statistical sampling in order to reliably interpret the experimental data is discussed.

Molecular dynamics simulations of protein folding and unfolding are often carried out at temperatures (400–600K) that are much higher than physiological or room temperature to speed up the (un)folding process. Use of such high temperatures changes both the protein and solvent properties considerably, compared to physiological or room temperature. Water models designed for use in conjunction with biomolecules, such as the simple point charge (SPC) model, have generally been calibrated at room temperature and pressure. To determine the distortive effect of high simulation temperatures on the behavior of such “room temperature” water models, the structural, dynamic, and thermodynamic properties of the much-used SPC water model are investigated in the temperature range from 300 to 500K. Both constant pressure and constant volume conditions, as used in protein simulations, were analyzed. We found that all properties analyzed change markedly with increasing temperature, but no phase transition in this temperature range was observed.

The ability to determine the free energy of solvation for a number of small organic molecules with varying sizes and properties from the coordinate trajectory of a single simulation of a given reference state was investigated. The relative free energies were estimated from a single step perturbation using the perturbation formula. The reference state consisted of a cavity surrounded by solvent. To enhance sampling a soft-core interaction was used for the cavity. The effect of the size of the cavity, the effective core height, and the length of simulation on the ability to reproduce results obtained from thermodynamic integration calculations was considered. The results using a single step perturbation from an appropriately chosen initial state were comparable to results from thermodynamic integration calculations for a wide range of compounds. Using a large number of compounds the computational efficiency was potentially increased by 2)3 orders of magnitude over traditional free energy approaches. Factors determining the efficiency of the approach are discussed. Q 1999 John Wiley & Sons, Inc. J Comput Chem 20: 1604)1617, 1999

Principal component analysis, also called essential dynamics, is a powerful tool for finding global, correlated motions in atomic simulations of macromolecules. It has become an established technique for analyzing molecular dynamics simulations of proteins. The first few principal components of simulations of large proteins often resemble cosines. We derive the principal components for high-dimensional random diffusion, which are almost perfect cosines. This resemblance between protein simulations and noise implies that for many proteins the time scales of current simulations are too short to obtain convergence of collective motions.

We describe a morphological image analysis method to characterize images in terms of geometry and topology. We present a method to compute the morphological properties of the objects building up the image and apply the method to triply periodic minimal surfaces and to images taken from polymer chemistry.

We describe a quantum computer emulator for a generic, general purpose quantum computer. This emulator consists of a simulator of the physical realization of the quantum computer and a graphical user interface to program and control the simulator. We illustrate the use of the quantum computer emulator through various implementations of the Deutsch-Jozsa and Grover's database search algorithm., Comment: 28 pages, 4, figures, see also http://rugth30.phys.rug.nl/compphys/qce.htm ; figures updated, instructions changed

Several series of site-directed mutations in thermolysin-like proteases are presented that show remarkable nonadditivity in their effect on thermal stability. A simple model is proposed that relates this nonadditivity to the occurrence of independent partial unfolding processes that occur in parallel at elevated temperatures. To prove this model, a thermolysin-like protease was designed in which two mutations located approximately 35 A apart in the structure individually exert small stabilizing effects of 2.3 and 4. 1 degreesC, respectively, but when combined stabilize the protease by 14.6 degreesC. This overadditivity, which follows directly from the model, confirms that unfolding of this engineered protease starts in parallel at two different regions of the protein.