Direct comparison of elastic incoherent neutron scattering experiments with molecular dynamics simulations of DMPC phase transitions.

Neutron scattering techniques have been employed to investigate 1,2-dimyristoyl-sn -glycero-3-phosphocholine (DMPC) membranes in the form of multilamellar vesicles (MLVs) and deposited, stacked multilamellar-bilayers (MLBs), covering transitions from the gel to the liquid phase. Neutron diffraction was used to characterise the samples in terms of transition temperatures, whereas elastic incoherent neutron scattering (EINS) demonstrates that the dynamics on the sub-macromolecular length-scale and pico- to nano-second time-scale are correlated with the structural transitions through a discontinuity in the observed elastic intensities and the derived mean square displacements. Molecular dynamics simulations have been performed in parallel focussing on the length-, time- and temperature-scales of the neutron experiments. They correctly reproduce the structural features of the main gel-liquid phase transition. Particular emphasis is placed on the dynamical amplitudes derived from experiment and simulations. Two methods are used to analyse the experimental data and mean square displacements. They agree within a factor of 2 irrespective of the probed time-scale, i.e. the instrument utilized. Mean square displacements computed from simulations show a comparable level of agreement with the experimental values, albeit, the best match with the two methods varies for the two instruments. Consequently, experiments and simulations together give a consistent picture of the structural and dynamical aspects of the main lipid transition and provide a basis for future, theoretical modelling of dynamics and phase behaviour in membranes. The need for more detailed analytical models is pointed out by the remaining variation of the dynamical amplitudes derived in two different ways from experiments on the one hand and simulations on the other.

Perspectives in biological physics: the nDDB project for a neutron Dynamics Data Bank for biological macromolecules.

Neutron spectroscopy provides experimental data on time-dependent trajectories, which can be directly compared to molecular dynamics simulations. Its importance in helping us to understand biological macromolecules at a molecular level is demonstrated by the results of a literature survey over the last two to three decades. Around 300 articles in refereed journals relate to neutron scattering studies of biological macromolecular dynamics, and the results of the survey are presented here. The scope of the publications ranges from the general physics of protein and solvent dynamics, to the biologically relevant dynamics-function relationships in live cells. As a result of the survey we are currently setting up a neutron Dynamics Data Bank (nDDB) with the aim to make the neutron data on biological systems widely available. This will benefit, in particular, the MD simulation community to validate and improve their force fields. The aim of the database is to expose and give easy access to a body of experimental data to the scientific community. The database will be populated with as much of the existing data as possible. In the future it will give value, as part of a bigger whole, to high throughput data, as well as more detailed studies. A range and volume of experimental data will be of interest in determining how quantitatively MD simulations can reproduce trends across a range of systems and to what extent such trends may depend on sample preparation and data reduction and analysis methods. In this context, we strongly encourage researchers in the field to deposit their data in the nDDB.

Dynamics-stability relationships in apo- and holomyoglobin: a combined neutron scattering and molecular dynamics simulations study.

The removal of the heme group from myoglobin (Mb) results in a destabilization of the protein structure. The dynamic basis of the destabilization was followed by comparative measurements on holo- (holo-Mb) and apomyoglobin (apo-Mb). Mean-squared displacements (MSD) and protein resilience on the picosecond-to-nanosecond timescale were measured by elastic incoherent neutron scattering. Differences in thermodynamic parameters, MSD, and resilience were observed for both proteins. The resilience of holo-Mb was significantly lower than that of apo-Mb, indicating entropic stabilization by a higher degree of conformational sampling in the heme-bound folded protein. Molecular dynamics simulations provided site-specific information. Averaged over the whole structure, the molecular dynamics simulations yielded similar MSD and resilience values for the two proteins. The mobility of residues around the heme group in holo-Mb showed a smaller MSD and higher resilience compared to the same residue group in apo-Mb. It is of interest that in holo-Mb, higher MSD values are observed for the residues outside the heme pocket, indicating an entropic contribution to protein stabilization by heme binding, which is in agreement with experimental results.

nMoldyn 3: using task farming for a parallel spectroscopy-oriented analysis of molecular dynamics simulations.

We present a new version of the program package nMoldyn, which has been originally developed for a neutron-scattering oriented analysis of molecular dynamics simulations of macromolecular systems (Kneller et al., Comput. Phys. Commun. 1995, 91, 191) and was later rewritten to include in-depth time series analyses and a graphical user interface (Rog et al., J. Comput. Chem. 2003, 24, 657). The main improvement in this new version and the focus of this article are the parallelization of all the analysis algorithms for use on multicore desktop computers as well as distributed-memory computing clusters. The parallelization is based on a task farming approach which maintains a simple program structure permitting easy modification and extension of the code to integrate new analysis methods.

Vibrational density of states of hydration water at biomolecular sites: hydrophobicity promotes low density amorphous ice behavior.

Inelastic neutron scattering experiments and molecular dynamics simulations have been used to investigate the low frequency modes, in the region between 0 and 100 meV, of hydration water in selected hydrophilic and hydrophobic biomolecules. The results show changes in the plasticity of the hydrogen-bond network of hydration water molecules depending on the biomolecular site. At 200 K, the measured low frequency density of states of hydration water molecules of hydrophilic peptides is remarkably similar to that of high density amorphous ice, whereas, for hydrophobic biomolecules, it is comparable to that of low density amorphous ice behavior. In both hydrophilic and hydrophobic biomolecules, the high frequency modes show a blue shift of the libration mode as compared to the room temperature data. These results can be related to the density of water molecules around the biological interface, suggesting that the apparent local density of water is larger in a hydrophilic environment.

In vivo molecular imaging of myocardial angiogenesis using the alpha(v)beta3 integrin-targeted tracer 99mTc-RAFT-RGD.

BACKGROUND: Myocardial angiogenesis following reperfusion of an infarcted area may impact on patient prognosis and pro-angiogenic treatments are currently evaluated. The non-invasive imaging of angiogenesis would therefore be of potential clinical relevance in these settings. (99m)Tc-RAFT-RGD is a novel (99m)Tc-labeled tracer that targets the alpha(v)beta(3) integrin. Our objective was to determine whether this tracer was suitable for myocardial angiogenesis imaging. METHODS AND RESULTS: A rat model of reperfused myocardial infarction was employed. Fourteen days following reperfusion, the animals were injected with (99m)Tc-RAFT-RGD or with its negative control (99m)Tc-RAFT-RAD. Fourteen animals were dedicated to autoradiographic imaging, infarct staining, and gamma-well counting of myocardial activity. In vivo dual-isotope pinhole SPECT imaging of (201)Tl and (99m)Tc-RAFT-RGD or (99m)Tc-RAFT-RAD was also performed in 11 additional animals. Neovessels were observed by immunostaining in the infarcted and peri-infarct areas. (99m)Tc-RAFT-RGD infarct-to-normal ratios by gamma-well counting and ex vivo imaging (2.5 +/- 0.6 and 4.9 +/- 0.9, respectively) were significantly higher than those of (99m)Tc-RAFT-RAD (1.7 +/- 0.2 and 2.2 +/- 0.4, respectively, P < .05). The infarcted area was readily visible in vivo by SPECT with (99m)Tc-RAFT-RGD but not with (99m)Tc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.5 +/- 0.6 and 1.7 +/- 0.4, respectively, P < .05). CONCLUSION: (99m)Tc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.

Transition events in one dimension.

The instanton or stationary-phase formula has received much attention recently as a way of determining transition paths in reacting systems. In this paper, we analyze the instanton approach for some one-dimensional problems and compare the results it gives with data from a numerical simulation. We show that a proper comparison of the analytic and numerical results must take into account the boundary conditions used in the numerical simulations and also suggest values for the integration constant in the instanton formula that gives the best agreement with the simulated results.

Evidence of dynamical constraints imposed by water organization around a bio-hydrophobic interface.

Molecular dynamics simulations and elastic neutron scattering experiments have been used to highlight how the structural organization of hydration water is able in some cases to locally constrain atomic movements at biologic interfaces. Using fully hydrated small peptides as models of protein interfaces, we show that the length of the side chains and the hydrophilic backbone have specific signatures. The dynamics of the side chain, which is part of biomolecules, have not only a crucial role in the whole flexibility as compared to the backbone, but also modify the values of transition temperatures. The analysis of the activation energies of methyl group dynamics suggests that the interaction between hydrophobic side chain and surrounding water plays an important role in the whole flexibility as well. We suggest that the progressive water cluster organization, around hydrophobic interfaces increases the activation energy and that a plateau regime is reached only when an extended hydrogen-bond network is established. The cluster size corresponds to a single layer of water molecules.

Use of structure descriptors to discriminate between modes of toxic action of phenols.

Two classification models were developed based on a data set of 220 phenols with four associated Modes of Toxic Action (MOA). Counter-propagation neural networks (CPG NN) and multinomial logistic regression (multinom) were used as classification methods. The combination of topological autocorrelation of empirical pi-charge and sigma-electronegativity and of surface autocorrelation of hydrogen-bonding potential resulted in a 21-dimensional model that successfully discriminated between the four MOAs. Its overall predictive power was estimated to 92% using 5-fold cross-validation. Subsequently, a simple score for the distance to the training data was used to determine the prediction space of the model and used in an exploratory study on the phenols contained in the open NCI database. The use of a prediction space metric proved indispensable for the screening of such a diverse database. The prediction space covered by the proposed model is still of rather local nature which is either caused by the limited diversity and size of the training set or by the high dimensionality of the descriptors.

Development and testing of a de novo drug-design algorithm.

In this article we present an implementation of a de novo drug-design algorithm. The algorithm starts with a molecule placed in the binding site of a protein and then modifies it using a sequential growth approach. This involves successive cycles of suppression of randomly picked groups in the molecule and their replacement by other groups chosen from databanks of linear or cyclic fragments. The algorithm has been coupled with the DYNAMO library which allows the simulation of macromolecules using molecular mechanical and quantum chemical methods. The main body of the article describes the methodologies we use to create, characterize and evaluate putative ligands. We also consider briefly an application of the algorithm to a protein of pharmacological interest, the neuraminidase of the influenza virus, and discuss the strengths and weaknesses of our approach.