Structural determinants in the bulk heterojunction.

Photovoltaics is one of the key areas in renewable energy research with remarkable progress made every year. Here we consider the case of a photoactive material and study its structural composition and the resulting consequences for the fundamental processes driving solar energy conversion. A multiscale approach is used to characterize essential molecular properties of the light-absorbing layer. A selection of bulk-representative pairs of donor/acceptor molecules is extracted from the molecular dynamics simulation of the bulk heterojunction and analyzed at increasing levels of detail. Significantly increased ground state energies together with an array of additional structural characteristics are identified that all point towards an auxiliary role of the material's structural organization in mediating charge-transfer and -separation. Mechanistic studies of the type presented here can provide important insights into fundamental principles governing solar energy conversion in next-generation photovoltaic devices.

Comparison of the accuracy of periodic reaction field methods in molecular dynamics simulations of a model liquid crystal system.

A periodic reaction field (PRF) method is a technique to estimate long-range interactions. The method has the potential to effectively reduce the computational cost while maintaining adequate accuracy. We performed molecular dynamics (MD) simulations of a model liquid-crystal system to assess the accuracy of some variations of the PRF method in low-charge-density systems. All the methods had adequate accuracy compared with the results of the particle mesh Ewald (PME) method, except for a few simulation conditions. Furthermore, in all of the simulation conditions, one of the PRF methods had the same accuracy as the PME method.

Structural features of aquaporin 4 supporting the formation of arrays and junctions in biomembranes.

A limited class of aquaporins has been described to form regular arrays and junctions in membranes. The biological significance of these structures, however, remains uncertain. Here we analyze the underlying physical principles with the help of a computational procedure that takes into account protein-protein as well as protein-membrane interactions. Experimentally observed array/junction structures are systematically (dis)assembled and major driving forces identified. Aquaporin 4 was found to be markedly different from the non-junction forming aquaporin 1. The environmental stabilization resulting from embedding into the biomembrane was identified as the main driving force. This highlights the role of protein-membrane interactions in aquaporin 4. Analysis of the type presented here can help to decipher the biological role of membrane arrays and junctions formed by aquaporin.

Common force field thermodynamics of cholesterol.

Four different force fields are examined for dynamic characteristics using cholesterol as a case study. The extent to which various types of internal degrees of freedom become thermodynamically relevant is evaluated by means of principal component analysis. More complex degrees of freedom (angle bending, dihedral rotations) show a trend towards force field independence. Moreover, charge assignments for membrane-embedded compounds are revealed to be critical with significant impact on biological reasoning.

GPU-accelerated computation of electron transfer.

Electron transfer is a fundamental process that can be studied with the help of computer simulation. The underlying quantum mechanical description renders the problem a computationally intensive application. In this study, we probe the graphics processing unit (GPU) for suitability to this type of problem. Time-critical components are identified via profiling of an existing implementation and several different variants are tested involving the GPU at increasing levels of abstraction. A publicly available library supporting basic linear algebra operations on the GPU turns out to accelerate the computation approximately 50-fold with minor dependence on actual problem size. The performance gain does not compromise numerical accuracy and is of significant value for practical purposes.

A combination of the tree-code and IPS method to simulate large scale systems by molecular dynamics.

An IPS/Tree method which is a combination of the isotropic periodic sum (IPS) method and tree-based method was developed for large-scale molecular dynamics simulations, such as biological and polymer systems, that need hundreds of thousands of molecules. The tree-based method uses a hierarchical tree structure to reduce the calculation cost of long-range interactions. IPS/Tree is an efficient method like IPS/DFFT, which is a combination of the IPS method and FFT in calculating large-scale systems that require massively parallel computers. The IPS method has two different versions: IPSn and IPSp. The basic idea is the same expect for the fact that the IPSn method is applied to calculations for point charges, while the IPSp method is used to calculate polar molecules. The concept of the IPS/Tree method is available for both IPSn and IPSp as IPSn/Tree and IPSp/Tree. Even though the accuracy of the Coulomb forces with tree-based method is well known, the accuracy for the combination of the IPS and tree-based methods is unclear. Therefore, in order to evaluate the accuracy of the IPS/Tree method, we performed molecular dynamics simulations for 32,000 bulk water molecules, which contains around 10(5) point charges. IPSn/Tree and IPSp/Tree were both applied to study the interaction calculations of Coulombic forces. The accuracy of the Coulombic forces and other physical properties of bulk water systems were evaluated. The IPSp/Tree method not only has reasonably small error in estimating Coulombic forces but the error was almost the same as the theoretical error of the ordinary tree-based method. These facts show that the algorithm of the tree-based method can be successfully applied to the IPSp method. On the other hand, the IPSn/Tree has a relatively large error, which seems to have been derived from the interaction treatment of the original IPSn method. The self-diffusion and radial distribution functions of water were calculated each by both the IPSn/Tree and IPSp/Tree methods, where both methods showed reasonable agreement with the Ewald method. In conclusion, the IPSp/Tree method is a potentially fast and sufficiently accurate technique for predicting transport coefficients and liquid structures of water in a homogeneous system.

Cutoff radius effect of the isotropic periodic sum and Wolf method in liquid-vapor interfaces of water.

As a more economical but similarly accurate computation method than the Ewald sum, the isotropic periodic sum (IPS) method for nonpolar molecules (IPSn) and polar molecules (IPSp), along with the Wolf method are of interest, but the cutoff radius dependence is an important issue. To evaluate the cutoff radius effect of the three methods, a water-vapor interfacial system has been studied by molecular dynamics. The Wolf method can produce adequate results for surface tension compared to that of the Ewald sum (within 2.9%) at a long enough cutoff radius, r(c). However, the estimation of the electrostatic potential profile and dipole orientational function is poor. The Wolf method cannot estimate electrostatic configuration at r(c) ≤ L(z)∕2 (L(z) is the longest lattice of the system). We have found that the convergence of the surface tension and the electrostatic configuration of the IPSn method is faster than that of the IPSp method. Moreover, the IPSn method is most accurate among the three methods for the same cutoff radius. Furthermore, the behavior of the surface tension against the cutoff radius shows a greater difference for the IPSn and IPSp method. The surface tension of the IPSp method fluctuates and presents a similar result to that of the Ewald sum, but the surface tension for the IPSn method greatly deviates near r(c) = L(z)∕3. The cause of this deviation is the difference between the interfacial configuration of the water surface and the cutoff treatment of the IPS method. The deviation becomes insignificant far from r(c) = L(z)∕3. In spite of this shortcoming, the IPSn method gives the most accurate result in estimating the surface tension at r(c) = L(z)∕2. From all the results in this work, the IPSn and IPSp method have been found to be more accurate than the Wolf method. In conclusion, the surface tension and structure of water-vapor interface can be calculated by the IPSn method when r(c) is greater than or equal to the longest lattice of the system. The IPSp method and the Wolf method require a longer cutoff radius than the longest lattice of the system to estimate interfacial properties.

Molecular dynamics simulations of vapor/liquid coexistence using the nonpolarizable water models.

The surface tension, vapor-liquid equilibrium densities, and equilibrium pressure for common water models were calculated using molecular dynamics simulations over temperatures ranging from the melting to the critical points. The TIP4P/2005 and TIP4P-i models produced better values for the surface tension than the other water models. We also examined the correlation of the data to scaling temperatures based on the critical and melting temperatures. The reduced temperature (T/T(c)) gives consistent equilibrium densities and pressure, and the shifted temperature T + (T(c, exp) - T(c, sim)) gives consistent surface tension among all models considered in this study. The modified fixed charge model which has the same Lennard-Jones parameters as the TIP4P-FQ model but uses an adjustable molecular dipole moment is also simulated to find the differences in the vapor-liquid coexistence properties between fixed and fluctuating charge models. The TIP4P-FQ model (2.72 Debye) gives the best estimate of the experimental surface tension. The equilibrium vapor density and pressure are unaffected by changes in the dipole moment as well as the surface tension and liquid density.

Thermodynamic properties of methane/water interface predicted by molecular dynamics simulations.

Molecular dynamics simulations have been performed to examine the thermodynamic properties of methane/water interface using two different water models, the TIP4P/2005 and SPC/E, and two sets of combining rules. The density profiles, interfacial tensions, surface excesses, surface pressures, and coexisting densities are calculated over a wide range of pressure conditions. The TIP4P/2005 water model was used, with an optimized combining rule between water and methane fit to the solubility, to provide good predictions of interfacial properties. The use of the infinite dilution approximation to calculate the surface excesses from the interfacial tensions is examined comparing the surface pressures obtained by different approaches. It is shown that both the change of methane solubilities in pressure and position of maximum methane density profile at the interface are independent of pressure up to about 2 MPa. We have also calculated the adsorption enthalpies and entropies to describe the temperature dependency of the adsorption.

High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations.

Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, this method is not completely reliable and therefore unsatisfactory. In this study, we used massive molecular dynamics simulations of protein-ligand conformations obtained by molecular docking in order to improve the enrichment performance of molecular docking. Our screening approach employed the molecular mechanics/Poisson-Boltzmann and surface area method to estimate the binding free energies. For the top-ranking 1,000 compounds obtained by docking to a target protein, approximately 6,000 molecular dynamics simulations were performed using multiple docking poses in about a week. As a result, the enrichment performance of the top 100 compounds by our approach was improved by 1.6-4.0 times that of the enrichment performance of molecular dockings. This result indicates that the application of molecular dynamics simulations to virtual screening for lead discovery is both effective and practical. However, further optimization of the computational protocols is required for screening various target proteins.

Cutoff radius effect of the isotropic periodic sum method in homogeneous system. II. Water.

Molecular dynamics simulation has been applied for water to compare the isotropic periodic sum (IPS) method [X. Wu and B. R. Brooks, J. Chem. Phys. 122, 044107 (2005)] with the Ewald sum based on the diffusion coefficient and liquid structure. The IPS method gives a good estimation for the self-diffusion coefficient at a cutoff radius, r(c), greater than 2.2 nm; however, the radial distribution function g(r) has a notable deviation. The peak of this deviation appears at specific intermolecular distances which are near each cutoff radius and decrease in proportion to the inverse of the cube of r(c). Thus the deviation becomes insignificant (less than 1%) at r(c) greater than 2.2 nm. The distance dependent Kirkwood factor G(k)(r) was also calculated, and since the truncation of a long-range interaction of the cutofflike method (such as cutoff with or without the switch function and the reaction field) shows serious shortcomings for dipole-dipole correlations in bulk water systems, this was observed by comparing the shape to that of the Ewald sum [Y. Yonetani, J. Chem. Phys. 124, 204501 (2006); D. van der Spoel and P. J. van Maaren, J. Chem. Theory Comput. 2, 1 (2006)]. The G(k)(r) of cutofflike method greatly deviate from that of the Ewald sum. However, the discrepancy of G(k)(r) for the IPS method was found to be much less than that of other typical cutofflike methods. In conclusion, the IPS method is an adequately accurate technique for estimating transport coefficients and the liquid structure of water in a homogeneous system at long cutoff distances.

Current performance gains from utilizing the GPU or the ASIC MDGRAPE-3 within an enhanced Poisson Boltzmann approach.

Scientific applications do frequently suffer from limited compute performance. In this article, we investigate the suitability of specialized computer chips to overcome this limitation. An enhanced Poisson Boltzmann program is ported to the graphics processing unit and the application specific integrated circuit MDGRAPE-3 and resulting execution times are compared to the conventional performance obtained on a modern central processing unit. Speed Up factors are measured and an analysis of numerical accuracy is provided. On both specialized architectures the improvement is increasing with problem size and reaches up to a Speed Up factor of 39 x for the largest problem studied. This type of alternative high performance computing can significantly improve the performance of demanding scientific applications.

An Improved Isotropic Periodic Sum Method That Uses Linear Combinations of Basis Potentials.

Isotropic periodic sum (IPS) is a technique that calculates long-range interactions differently than conventional lattice sum methods. The difference between IPS and lattice sum methods lies in the shape and distribution of remote images for long-range interaction calculations. The images used in lattice sum calculations are identical to those generated from periodic boundary conditions and are discretely positioned at lattice points in space. The images for IPS calculations are "imaginary", which means they do not explicitly exist in a simulation system and are distributed isotropically and periodically around each particle. Two different versions of the original IPS method exist. The IPSn method is applied to calculations for point charges, whereas the IPSp method calculates polar molecules. However, both IPSn and IPSp have their advantages and disadvantages in simulating bulk water or water-vapor interfacial systems. In bulk water systems, the cutoff radius effect of IPSn strongly affects the configuration, whereas IPSp does not provide adequate estimations of water-vapor interfacial systems unless very long cutoff radii are used. To extend the applicability of the IPS technique, an improved IPS method, which has better accuracy in both homogeneous and heterogeneous systems has been developed and named the linear-combination-based isotropic periodic sum (LIPS) method. This improved IPS method uses linear combinations of basis potentials. We performed molecular dynamics (MD) simulations of bulk water and water-vapor interfacial systems to evaluate the accuracy of the LIPS method. For bulk water systems, the LIPS method has better accuracy than IPSn in estimating thermodynamic and configurational properties without the countercharge assumption, which is used for IPSp. For water-vapor interfacial systems, LIPS has better accuracy than IPSp and properly estimates thermodynamic and configurational properties. In conclusion, the LIPS method can successfully estimate homogeneous and heterogeneous systems of polar molecular systems with good accuracy.

Cutoff radius effect of isotropic periodic sum method for transport coefficients of Lennard-Jones liquid.

Molecular dynamics simulations of a Lennard-Jones (LJ) liquid were applied to compare the isotropic periodic sum (IPS) method [X. Wu and B. R. Brooks, J. Chem. Phys. 122, 044107 (2005)], which can reduce the calculation cost of long-range interactions, such as the Lennard-Jones and Coulombic ones, with the cutoff method for the transport coefficients which includes the self-diffusion coefficient, bulk viscosity, and thermal conductivity. The self-diffusion coefficient, bulk viscosity, and thermal conductivity were estimated with reasonable accuracy if the cutoff distance of the LJ potential for the IPS method was greater than 3sigma. The IPS method is an effective technique for estimating the transport coefficients of the Lennard-Jones liquid in a homogeneous system.

Folding dynamics of 10-residue beta-hairpin peptide chignolin.

Short peptides that fold into beta-hairpins are ideal model systems for investigating the mechanism of protein folding because their folding process shows dynamics typical of proteins. We performed folding, unfolding, and refolding molecular dynamics simulations (total of 2.7 micros) of the 10-residue beta-hairpin peptide chignolin, which is the smallest beta-hairpin structure known to be stable in solution. Our results revealed the folding mechanism of chignolin, which comprises three steps. First, the folding begins with hydrophobic assembly. It brings the main chain together; subsequently, a nascent turn structure is formed. The second step is the conversion of the nascent turn into a tight turn structure along with interconversion of the hydrophobic packing and interstrand hydrogen bonds. Finally, the formation of the hydrogen-bond network and the complete hydrophobic core as well as the arrangement of side-chain-side-chain interactions occur at approximately the same time. This three-step mechanism appropriately interprets the folding process as involving a combination of previous inconsistent explanations of the folding mechanism of the beta-hairpin, that the first event of the folding is formation of hydrogen bonds and the second is that of the hydrophobic core, or vice versa.

Structure and dynamics of RNA polymerase II elongation complex.

RNA polymerase (Pol) II is a fundamental and important enzyme in the transcription process. However, two mysterious questions have remained unsolved: how an unwound bubble of DNA is established and maintained, and how the enzyme moves along the DNA. To answer these questions, we constructed a model structure of the Pol II elongation complex with the 50 base pairs of DNA-24 bases of RNA including the unwound bubble of DNA and performed a molecular dynamics simulation. We obtained a reliable model structure of the Pol II elongation complex in the pre-translocation state which has not yet been determined by the X-ray crystallographic study. The model structure revealed that multiple protein loops work concertedly to form and maintain the bubble structure. We also found that the conformational change of a loop in the Pol II, fork loop 1, couples with the unidirectional movement of the Pol II along the DNA.

Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides.

Ligand-activated and tyrosine-phosphorylated ErbB3 receptor binds to the SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase and initiates intracellular signaling. Here, we studied the interactions between the N- (N-SH2) and C- (C-SH2) terminal SH2 domains of the p85 subunit of the phosphatidylinositol 3-kinase and eight ErbB3 receptor-derived phosphotyrosyl peptides (P-peptides) by using molecular dynamics, free energy, and surface plasmon resonance (SPR) analyses. In SPR analysis, these P-peptides showed no binding to the C-SH2 domain, but P-peptides containing a phospho-YXXM or a non-phospho-YXXM motif did bind to the N-SH2 domain. The N-SH2 domain has two phosphotyrosine binding sites in its N- (N1) and C- (N2) terminal regions. Interestingly, we found that P-peptides of pY1180 and pY1241 favored to bind to the N2 site, although all other P-peptides showed favorable binding to the N1 site. Remarkably, two phosphotyrosines, pY1178 and pY1243, which are just 63 amino acids apart from the pY1241 and pY1180, respectively, showed favorable binding to the N1 site. These findings indicate a possibility that the pair of phosphotyrosines, pY1178-pY1241 or pY1243-pY1180, will fold into an appropriate configuration for binding to the N1 and N2 sites simultaneously. Our model structures of the cytoplasmic C-terminal domain of ErbB3 receptor also strongly supported the speculation. The calculated binding free energies between the N-SH2 domain and P-peptides showed excellent qualitative agreement with SPR data with a correlation coefficient of 0.91. The total electrostatic solvation energy between the N-SH2 domain and P-peptide was the dominant factor for its binding affinity.

Molecular dynamics, free energy, and SPR analyses of the interactions between the SH2 domain of Grb2 and ErbB phosphotyrosyl peptides.

We studied the interactions between the SH2 domain of growth factor receptor binding protein 2 (Grb2) and ErbB receptor-derived phosphotyrosyl peptides using molecular dynamics, free energy calculations, and surface plasmon resonance (SPR) analysis. Binding free energies for nine phosphotyrosyl peptides were calculated using the MM-PBSA continuum solvent method, and excellent qualitative agreement with the SPR experimental data, with a correlation coefficient of 0.92, was obtained. Consistent with previous experimental findings, phosphotyrosyl peptides with the consensus sequence pYXNX showed favorable binding affinity for the Grb2. Unexpectedly, phosphotyrosyl peptides with the consensus sequence pYQQD, which had not shown any specific binding affinity for the Grb2 in earlier studies, also showed favorable binding affinity for the Grb2 in our experimental and computational analyses. Component analysis of the calculated binding free energies revealed that van der Waals interaction between the Grb2 and the phosphotyrosyl peptide was the dominant factor for specificity and binding affinity. These results indicate that current methods of estimating binding free energies are efficient for obtaining important information about protein-protein interactions, which are essential for the transmission of signals in cellular signaling pathways.

Tyr-317 phosphorylation increases Shc structural rigidity and reduces coupling of domain motions remote from the phosphorylation site as revealed by molecular dynamics simulations.

Activated receptor tyrosine kinases bind the Shc adaptor protein through its N-terminal phosphotyrosine-binding (PTB) and C-terminal Src homology 2 (SH2) domains. After binding, Shc is phosphorylated within the central collagen-homology (CH) linker region on Tyr-317, a residue remote to both the PTB and SH2 domains. Shc phosphorylation plays a pivotal role in the initiation of mitogenic signaling through the Ras/Raf/MEK/ERK pathway, but it is unclear if Tyr-317 phosphorylation affects Shc-receptor interactions through the PTB and SH2 domains. To investigate the structural impact of Shc phosphorylation, molecular dynamics simulations were carried out using special-purpose Molecular Dynamics Machine-Grape computers. After a 1-nanosecond equilibration, atomic motions in the structures of unphosphorylated Shc and Shc phosphorylated on Tyr-317 were calculated during a 2-nanosecond period. The results reveal larger phosphotyrosine-binding domain fluctuations and more structural flexibility of unphosphorylated Shc compared with phosphorylated Shc. Collective motions between the PTB-SH2, PTB-CH, and CH-SH2 domains were highly correlated only in unphosphorylated Shc. Dramatic changes in domain coupling and structural rigidity, induced by Tyr-317 phosphorylation, may alter Shc function, bringing about marked differences in the association of unphosphorylated and phosphorylated Shc with its numerous partners, including activated membrane receptors.