Molecular Dynamics Simulations of Proteins in Water Without the Truncation of Long-range Coulomb Interactions

A new program package (COSMOS90) for molecular dynamics simulations was developed to simulate large molecular systems consisting of more than tens of thousands of atoms without the truncation of long-range coulomb interactions. This program package was based on a new approximation scheme (PPPC) for calculating efficiently the coulomb interactions without sacrificing accuracy. In this approximation scheme, the group of charges at a long distance from each atom was represented by a total charge and total dipole moment of the group. In order to assess the accuracy of PPPC and the ability of COSMOS90, molecular dynamics simulations were carried out for a large system consisting of 16108 atoms (human lysozyme in water) for 50 ps using this program package. The coulomb energy per solute atom was calculated with only five percent of the error found in the 10 Å cut-off approximation (about 0.9 kcal/mol versus 18 kcal/mol, respectively). The molecular dynamics simulations using COSMOS90 require no more CPU time than the simulations based on the 10 Å cut-off approximation of the conventional programs for macromolecular simulations.     

Datamonkey: rapid detection of selective pressure on individual sites of codon alignments

Datamonkey is a web interface to a suite of cutting edge maximum likelihood-based tools for identification of sites subject to positive or negative selection. The methods range from very fast data exploration to the some of the most complex models available in public domain software, and are implemented to run in parallel on a cluster of computers. AVAILABILITY: http://www.datamonkey.org. In the future, we plan to expand the collection of available analytic tools, and provide a package for installation on other systems.     

High performance computing in biology: multimillion atom simulations of nanoscale systems

Computational methods have been used in biology for sequence analysis (bioinformatics), all-atom simulation (molecular dynamics and quantum calculations), and more recently for modeling biological networks (systems biology). Of these three techniques, all-atom simulation is currently the most computationally demanding, in terms of compute load, communication speed, and memory load. Breakthroughs in electrostatic force calculation and dynamic load balancing have enabled molecular dynamics simulations of large biomolecular complexes. Here, we report simulation results for the ribosome, using approximately 2.64 million atoms, the largest all-atom biomolecular simulation published to date. Several other nano-scale systems with different numbers of atoms were studied to measure the performance of the NAMD molecular dynamics simulation program on the Los Alamos National Laboratory Q Machine. We demonstrate that multimillion atom systems represent a 'sweet spot' for the NAMD code on large supercomputers. NAMD displays an unprecedented 85% parallel scaling efficiency for the ribosome system on 1024 CPUs. We also review recent targeted molecular dynamics simulations of the ribosome that prove useful for studying conformational changes of this large biomolecular complex in atomic detail.     

Quantitative protein microarrays for time-resolved measurements of protein phosphorylation

The quantitative analysis of signaling networks requires highly sensitive methods for the time-resolved determination of protein phosphorylation. For this reason, we developed a quantitative protein microarray that monitors the activation of multiple signaling pathways in parallel, and at high temporal resolution. A label-free sandwich approach was combined with near infrared detection, thus permitting the accurate quantification of low-level phosphoproteins in limited biological samples corresponding to less than 50,000 cells, and with a very low standard deviation of approximately 5%. The identification of suitable antibody pairs was facilitated by determining their accuracy and dynamic range using our customized software package Quantpro. Thus, we are providing an important tool to generate quantitative data for systems biology approaches, and to drive innovative diagnostic applications.     

Structural modeling of the distamycin A-d(CGCGAATTCGCG)2 complex using 2D NMR and molecular mechanics

The structure of the distamycin A-d(CGCGAATTCGCG)2 complex has been determined through a combination of SKEWSKY and NOESY 2D NMR experiments and molecular mechanics calculations. NMR data provided upper bounds on many proton-proton pairs. The advantage of the SKEWSKY/NOESY method is that small groups of strongly coupled spins can be treated accurately as isolated systems. The AMBER molecular mechanics package, modified to include the NMR constraints, was used in energy refinements. Distamycin A fits snugly into the 5'-AATT-3' minor-groove binding site. Structural analysis revealed van der Waals contacts between A5, A6, and A18 C2H and drug H3 protons, potential three-center hydrogen bonding between drug amide protons and adenine N3 and thymine O2 atoms analogous to the spine of hydration in the crystal structure of the free DNA, and stacking of the sugar O1' atoms of A6-C21, T7-T20, and, T8-T19, over drug pyrrole rings 1, 2, and 3, respectively. In addition to hydrophobic effects, hydrogen bonding, and electrostatic interactions proposed by others, it is suggested that stacking interactions between DNA sugar O1' atoms and the three drug pyrrole rings contribute to the stability of the complex.     

TREE-PUZZLE: maximum likelihood phylogenetic analysis using quartets and parallel computing

SUMMARY: TREE-PUZZLE is a program package for quartet-based maximum-likelihood phylogenetic analysis (formerly PUZZLE, Strimmer and von Haeseler, Mol. Biol. Evol., 13, 964-969, 1996) that provides methods for reconstruction, comparison, and testing of trees and models on DNA as well as protein sequences. To reduce waiting time for larger datasets the tree reconstruction part of the software has been parallelized using message passing that runs on clusters of workstations as well as parallel computers. AVAILABILITY: http://www.tree-puzzle.de. The program is written in ANSI C. TREE-PUZZLE can be run on UNIX, Windows and Mac systems, including Mac OS X. To run the parallel version of PUZZLE, a Message Passing Interface (MPI) library has to be installed on the system. Free MPI implementations are available on the Web (cf. http://www.lam-mpi.org/mpi/implementations/).     

Large Scale Molecular Dynamics on Parallel Computers using the Link-cell Algorithm

Parallel computers offer a more cost-effective route to high performance computing than traditional single processor machines. Software for such machines is still in its infancy and they are often much more difficult to program than sequential machines. In addition many of the algorithms which are successful with sequential and vector processors are no longer appropriate. Both the force calculation and integration steps of molecular dynamics are parallel in nature and for that reason we have developed a parallel algorithm based on the link cell technique. This method is particularly efficient when the range of intermolecular potential is much smaller than the dimensions of the simulation box. The details of the algorithm are presented for systems of atoms in two and three dimensions using a number of decompositions into sub-units. The algorithm has been tested on an Intel iPSC/2 and a Cray X-MP/416 and the results are presented for simulations of up to 2 · 10⁶ atoms.     

DL_POLY_2.0: A general-purpose parallel molecular dynamics simulation package

DL_POLY_2.0 is a general-purpose parallel molecular dynamics simulation package developed at Daresbury Laboratory under the auspices of the Council for the Central Laboratory of the Research Councils. Written to support academic research, it has a wide range of applications and is designed to run on a wide range of computers: from single processor workstations to parallel supercomputers. Its structure, functionality, performance, and availability are described.     

Generation of initial molecular dynamics configurations in arbitrary geometries and in parallel

A computational pre-processing tool for generating initial configurations of molecules for molecular dynamics simulations in geometries described by a mesh of unstructured arbitrary polyhedra is described. The mesh is divided into separate zones and each can be filled with a single crystal lattice of atoms. Each zone is filled by creating an expanding cube of crystal unit cells, initiated from an anchor point for the lattice. Each unit cell places the appropriate atoms for the user-specified crystal structure and orientation. The cube expands until the entire zone is filled with the lattice; zones with concave and disconnected volumes may be filled. When the mesh is spatially decomposed into portions for distributed parallel processing, each portion may be filled independently, meaning that the entire molecular system never needs to fit onto a single processor, allowing very large systems to be created. The computational time required to fill a zone with molecules scales linearly with the number of cells in the zone for a fixed number of molecules, and better than linearly with the number of molecules for a fixed number of mesh cells. Our tool, molConfig, has been implemented in the open source C++ code OpenFOAM.     

NEUREC - a program package for 3D-reconstruction from serial sections using a microcomputer

A software package is described to reconstruct three-dimensional pictures in true perspective from a series of parallel sections using a low-cost computer system (Apple II plus). Data sampling via a graphic tablet and graphical output on the monitor screen or a digital plotter are assigned to different programs under control of a menu program. The number of data representing the object under study is unlimited. Originally written in BASIC, the programs were translated to machine language. As an application of the package, reconstructions of an identified large interneuron of the locust brain are presented.     

P2BAT: a massive parallel implementation of PBAT for genome-wide association studies in R

The software tool P2BAT provides a massive parallel and user friendly implementation of the PBAT-analysis tools for family-based association tests (FBATs) in large-scale studies, including genome-wide association studies with several thousand subjects. Built on the original PBAT-implementation of the Lange-Van Steen algorithm to bypass the multiple testing problem in family-based association studies, P2BAT integrates all PBAT-analysis tools for binary and complex traits into R and makes them accessible through a user-friendly GUI. The genome-wide analysis tools are fully automated and can be ran massively parallel directly through the GUI. P2BAT is fully documented and contains graphical output tools for time-to-onset analysis. P2BAT also features the ability to test for gene and environment/drug interaction. AVAILABILITY: The P2BAT package is available as the R package 'pbatR' which can be downloaded from http://cran.r-project.org/. The PBAT-software is available at http://www.biostat.harvard.edu/~clange/.     

Nonorthogonal tight-binding model with H–C–N–O parameterisation

A parametric nonorthogonal tight-binding model (NTBM1) with the set of parameters for H–C–N–O systems is presented. This model compares well with widely used semi-empirical AM1 and PM3/PM7 models but contains less fitting parameters per atom. All NTBM1 parameters are derived based on a criterion of the best agreement between the calculated and experimental values of bond lengths, valence angles and binding energies for various H–C–N–O molecules. Results for more than 200 chemical compounds are reported. Parameters are currently available for hydrogen, carbon, nitrogen, oxygen atoms and corresponding interatomic interactions. The model has a good transferability and can be used for both relaxation of large molecular systems (e.g., high-molecular compounds or covalent cluster complexes) and long-timescale molecular dynamics simulation (e.g., modelling of thermal decomposition processes). The program package based on this model is available for download at no cost from http://ntbm.info.     

BioBayes: a software package for Bayesian inference in systems biology

MOTIVATION: There are several levels of uncertainty involved in the mathematical modelling of biochemical systems. There often may be a degree of uncertainty about the values of kinetic parameters, about the general structure of the model and about the behaviour of biochemical species which cannot be observed directly. The methods of Bayesian inference provide a consistent framework for modelling and predicting in these uncertain conditions. We present a software package for applying the Bayesian inferential methodology to problems in systems biology. RESULTS: Described herein is a software package, BioBayes, which provides a framework for Bayesian parameter estimation and evidential model ranking over models of biochemical systems defined using ordinary differential equations. The package is extensible allowing additional modules to be included by developers. There are no other such packages available which provide this functionality.     

The NUCOMBog R package for simulating vegetation,water, carbon and nitrogen dynamics in peatlands

Since peatlands store up to 30% of the global soil organic carbon, it is important to understand how these ecosystems will react to a change in climate and management. Process-based ecosystem models have emerged as important tools for predicting long-term peatland dynamics, but their application is often challenging because they require programming skills. In this paper, we present NUCOMBog, an R package of the NUCOM-Bog model (Heijmans et al. 2008), which simulates the vegetation, carbon, nitrogen and water dynamics of peatlands in monthly time steps. The package complements the model with appropriate functions, such as the calculation of net ecosystem exchange, as well as parallel functionality. As a result, the NUCOMBog R package provides a user-friendly tool for simulating vegetation and biogeochemical cycles/fluxes in peatlands over years/decades, under different management strategies and climate change scenarios, with the option to use all the in-built model analysis capabilities of R, such as plotting, sensitivity analysis or optimization.     

Solving the problem of building models of crosslinked polymers: an example focussing on validation of the properties of crosslinked epoxy resins

The construction of molecular models of crosslinked polymers is an area of some difficulty and considerable interest. We report here a new method of constructing these models and validate the method by modelling three epoxy systems based on the epoxy monomers bisphenol F diglycidyl ether (BFDGE) and triglycidyl-p-amino phenol (TGAP) with the curing agent diamino diphenyl sulphone (DDS). The main emphasis of the work concerns the improvement of the techniques for the molecular simulation of these epoxies and specific attention is paid towards model construction techniques, including automated model building and prediction of glass transition temperatures (T(g)). Typical models comprise some 4200-4600 atoms (ca. 120-130 monomers). In a parallel empirical study, these systems have been cast, cured and analysed by dynamic mechanical thermal analysis (DMTA) to measure T(g). Results for the three epoxy systems yield good agreement with experimental T(g) ranges of 200-220°C, 270-285°C and 285-290°C with corresponding simulated ranges of 210-230°C, 250-300°C, and 250-300°C respectively.     

Lycopene,but not zeaxanthin,serves as a skeleton for the formation of an orthorhombic organization of intercellular lipids within the lamellae in the stratum corneum: Molecular dynamics simulations of the hydrated ceramide NS bilayer model

Carotenoids play an important role in the protection of biomembranes against oxidative damage. Their function depends on the surroundings and the organization of the lipid membrane they are embedded in. Carotenoids are located parallel or perpendicular to the surface of the lipid bilayer. The influence of carotenoids on the organization of the lipid bilayer in the stratum corneum has not been thoroughly considered. Here, the orientation of the exemplary cutaneous carotenoids lycopene and zeaxanthin in a hydrated ceramide NS24 bilayer model and the influence of carotenoids on the lateral organization of the lipid bilayer model were studied by means of molecular dynamics simulations for 32 °C and 37 °C. The results confirm that lycopene is located parallel and zeaxanthin perpendicular to the surface of the lipid bilayer. The lycopene-loaded lipid bilayer appeared to have a strong orthorhombic organization, while zeaxanthin-loaded and pure lipid bilayers were organized in a disordered hexagonal-like and liquid-like state, respectively. The effect is stronger at 32 °C compared to 37 °C based on p-values. Therefore, it was assumed that carotenoids without hydroxyl polar groups in their structure facilitate the formation of the orthorhombic organization of lipids, which provides the skin barrier function. It was shown that the distance between carotenoid atoms matched the distance between atoms in the lipids, indicating that parallel located carotenoids without hydroxyl groups serve as a skeleton for lipid membranes inside the lamellae. The obtained results provide reasonable prediction of the overall qualitative properties of lipid model systems and show the importance of parallel-oriented carotenoids in the development and maintenance of the skin barrier function.     

Binding of 2-formylpyridine monothiosemicarbazonato copper II to cat and normal human hemoglobins

The antitumor agent 2-formylpyridine monothiosemicarbazonato copper(II) forms adducts with sulfur and nitrogen donor atoms from cat hemoglobin but only nitrogen donor atoms from human hemoglobin. Improved resolution of the mI = 1/2 lines in the g parallel region at S-band not only confirms the number of nitrogen donor atoms in the square planar configuration but provides evidence for strong coupling from a proton. Adduct formation results in an increase in the oxygen affinity of hemoglobin. Thus, it is suggested that allosteric enzyme inhibition may be a mechanism for the action of this agent.     

Spherical tensor multipolar electrostatics and smooth particle mesh Ewald summation: a theoretical study

The point-charge approximation, typically used by classical molecular mechanics force-fields, can be overcome by a multipolar expansion. For decades multipole moments were only used in the context of the rigid body approximation but recently it has become possible to combine multipolar electrostatics with molecular flexibility. The program DL_MULTI, which is derived from DL_POLY_2, includes efficient multipolar Ewald functionality up to the hexadecapole moment but the code is restricted to rigid bodies. The incorporation of flexibility into DL_MULTI would cause too large an impact on its architecture whereas the package DL_POLY_4 offers a more attractive and sustainable route to handle multipolar electrostatics. This package inherently handles molecular flexibility, which warrants sufficiently transferable atoms or atoms that are “knowledgeable” about their chemical environment (as made possible by quantum chemical topology and machine learning). DL_MULTI uses the spherical multipole formalism, which is mathematically more involved than the Cartesian one but which is more compact. DL_POLY_4 uses the computationally efficient method of smooth particle mesh Ewald (SPME) summation, which has also been parallellized by others. Therefore, combining the strengths of DL_POLY_4 and DL_MULTI poses the challenge of merging SPME with multipolar electrostatics by spherical multipole. In an effort to recast as clearly as possible the principles behind DL_MULTI, its key equations have been reformulated by the more streamlined route involving the algebra of complex numbers, and some of these equations’ peculiarities clarified. This article explores theoretically the repercussions of the merging of SPME with spherical multipole electrostatics (as implemented in DL_MULTI). Difficulties in design and implementation of possible future code are discussed.     

Interaction centres of purine nucleotides: adenosine-5'-diphosphate and adenosine-5'-triphosphate in their reactions with tetramines and Cu(II) ions

The interactions between the nucleotides: adenosine-5'-diphosphate (ADP) and adenosine-5'-triphosphate (ATP) with spermine (Spm) and 1,11-diamine-4,8-diazaundecane (3,3,3-tet), as well as Cu(II) ions are studied. In the metal-free systems nucleotide-polyamine molecular complexes have been found to form, in which the interaction centres are the nitrogen atoms of the purine ring N(1) and N(7), oxygen atoms of the phosphate group of the nucleotide (for 3,3,3-tet) and protonated nitrogen atoms of the polyamine. Significant differences in the mode of metallation between the systems with Spm and 3,3,3-tet have been established. In the systems with Spm, the main products are protonated species with [N(7),O] chromophore and the nitrogen N(1) is involved in the intramolecular interaction additionally stabilising the complex. In the systems with 3,3,3-tet the formation of metal-ligand-ligand (MLL) species has been observed, in which the oxygen atoms from the phosphate group and the nitrogen atoms from the polyamine are involved in the metallation, while the N(1) and N(7) atoms from the purine ring of the nucleotide remain outside the inner coordination sphere of the copper ion. The main centre of metallation in the nucleotide, both with Spm and 3,3,3-tet, is the phosphate group of the nucleotide.