Tensile Strength of Liquids: Equivalence of Temporal and Spatial Scales in Cavitation.

It is well known that strain rate and size effects are both important in material failure, but the relationships between them are poorly understood. To establish this connection, we carry out molecular dynamics (MD) simulations of cavitation in Lennard-Jones and Cu liquids over a very broad range of size and strain rate. These studies confirm that temporal and spatial scales play equivalent roles in the tensile strengths of these two liquids. Predictions based on smallest-scale MD simulations of Cu for larger temporal and spatial scales are consistent with independent simulations, and comparable to experiments on liquid metals. We analyze these results in terms of classical nucleation theory and show that the equivalence arises from the role of both size and strain rate in the nucleation of a daughter phase. Such equivalence is expected to hold for a wide range of materials and processes and to be useful as a predictive bridging tool in multiscale studies.

Direct MD Simulations of Terahertz Absorption and 2D Spectroscopy Applied to Explosive Crystals.

A direct molecular dynamics simulation of the THz spectrum of a molecular crystal is presented. A time-dependent electric field is added to a molecular dynamics simulation of a crystal slab. The absorption spectrum is composed from the energy dissipated calculated from a series of applied pulses characterized by a carrier frequency. The spectrum of crystalline cyclotrimethylenetrinitramine (RDX) and triacetone triperoxide (TATP) were simulated with the ReaxFF force field. The proposed direct method avoids the linear response and harmonic approximations. A multidimensional extension of the spectroscopy is suggested and simulated based on the nonlinear response to a single polarized pulse of radiation in the perpendicular polarization direction.

Shock response of single crystal and nanocrystalline pentaerythritol tetranitrate: Implications to hotspot formation in energetic materials.

We investigate shock response of single crystal and nanocrystalline pentaerythritol tetranitrate (PETN) with a coarse-grained model and molecular dynamics simulations, as regards mechanical hotspot formation in the absence or presence of grain boundaries (GBs). Single crystals with different orientations, and columnar nanocrystalline PETN with regular hexagonal, irregular hexagonal, and random GB patterns, are subjected to shock loading at different shock strengths. In single crystals, shock-induced plasticity is consistent with resolved shear stress calculations and the steric hindrance model, and this deformation leads to local heating. For regular-shaped hexagonal columnar nanocrystalline PETN, different misorientation angles lead to activation of different/same slip systems, different deformation in individual grains and as a whole, different GB friction, different temperature distributions, and then, different hotspot characteristics. Compared to their regular-shaped hexagonal counterpart, nanocrystalline PETN with irregular hexagonal GB pattern and that with random GBs, show deformation and hotspot features specific to their GBs. Driven by stress concentration, hotspot formation is directly related to GB friction and GB-initiated crystal plasticity, and the exact deformation is dictated by grain orientations and resolved shear stresses. GB friction alone can induce hotspots, but the hotspot temperature can be enhanced if it is coupled with GB-initiated crystal plasticity, and the slip of GB atoms has components out of the GB plane. The magnitude of shearing can correlate well with temperature, but the slip direction of GB atoms relative to GBs may play a critical role. Wave propagation through varying microstructure may also induce differences in stress states (e.g., stress concentrations) and loading rates, and thus, local temperature rise. GB-related friction and plasticity induce local heating or mechanical hotspots, which could be precursors to chemical hotspot formation related to initiation in energetic materials, in the absence of other, likely more effective, means for hotspot formation such as void collapse.

Nanometallic glasses: size reduction brings ductility, surface state drives its extent.

We report tensile experiments on Ni80P20 metallic glass samples fabricated via a templated electroplating process and via focused ion beam milling, which differed only in their surface energy states: Ga-ion-irradiated and as-electroplated. Molecular dynamics simulations on similar Ni80Al20 systems corroborate the experimental results, which suggest that the transition from brittle to ductile behavior is driven by sample size, while the extent of ductility is driven by surface state.

Computational modeling of structure-function of g protein-coupled receptors with applications for drug design.

G protein-coupled receptors (GPCRs) mediate senses such as odor, taste, vision, and pain in mammals. In addition, important cell recognition and communication processes often involve GPCRs. Many diseases involve malfunction of GPCRs, making them important targets for drug development. Indeed, greater than 50 % of all marketed therapeutics act on those receptors. Unfortunately, the atomic-level structures are only available for rhodopsin, beta2AR, beta1AR, A2A adenosin and opsin. In silico computational methods, employing receptor-based modeling, offer a rational approach in the design of drugs targeting GPCRs. These approaches can be used to understand receptor selectivity and species specificity of drugs that interact with GPCRs. This review gives an overview of current computational approaches to GPCR model building; ligand-receptor interaction for drug design; and molecular mechanism of GPCR activation from simulation.

Predicting solid-state heats of formation of newly synthesized polynitrogen materials by using quantum mechanical calculations.

We present density functional theory level predictions and analysis of the basic properties of newly synthesized high-nitrogen compounds together with 3,6-bis(2H-tetrazol-5-yl)-1,2,4,5-tetrazine (BTT) and 3,3'-azobis(6-amino-1,2,4,5-tetrazine) (DAAT), for which experimental data are available. The newly synthesized high-nitrogen compounds are based on tricycle fused 1,2,4-triazine and 1,2,4,5-tetrazine heterocycles. In this work, the molecules BTT and DAAT have been studied in order to validate the theoretical approach and to facilitate further progress developments for the molecules of interest. Molecular structural properties are clarified, and IR spectra predictions are provided to help detection of those compounds in the experiment. The energy content of the molecules in the gas phase is evaluated by calculating standard enthalpies of formation, by using a special selection of isodesmic reaction paths. We also include estimates of the condensed-phase heats of formation and heats of sublimation in the framework of the Politzer approach. The obtained properties are consistent with those new high-nitrogen compounds being a promising set of advanced energetic materials.

Quantum Chemical Calculations of the Influence of Anchor-Cum-Spacer Groups on Femtosecond Electron Transfer Times in Dye-Sensitized Semiconductor Nanocrystals.

Electronic properties of dye-sensitized semiconductor nanocrystals, consisting of perylene (Pe) chromophores attached to 2 nm TiO2 nanocrystals via different anchor-cum-spacer groups, have been studied theoretically using density functional theory (DFT) cluster calculations. Approximate effective electronic coupling strengths for the heterogeneous electron-transfer interaction have been extracted from the calculated electronic structures and are used to estimate femtosecond electron-transfer times theoretically. Results are presented for perylenes attached to the TiO2 via formic acid (Pe-COOH), propionic acid (Pe-CH2-CH2-COOH), and acrylic acid (Pe-CH [Formula: see text] CH-COOH). The calculated electron transfer times are between 5 and 10 fs with the formic acid and the conjugated acrylic acid bridges and about 35 fs with the saturated propionic acid bridge. The calculated electron injection times are of the same order of magnitude as the corresponding experimental values and qualitatively follow the experimental trend with respect to the influence of the different substitutions on the injection times.

Hildebrand and Hansen solubility parameters from molecular dynamics with applications to electronic nose polymer sensors.

We introduce the Cohesive Energy Density (CED) method, a multiple sampling Molecular Dynamics computer simulation procedure that may offer higher consistency in the estimation of Hildebrand and Hansen solubility parameters. The use of a multiple sampling technique, combined with a simple but consistent molecular force field and quantum mechanically determined atomic charges, allows for the precise determination of solubility parameters in a systematic way (sigma = 0.4 hildebrands). The CED method yields first-principles Hildebrand parameter predictions in good agreement with experiment [root-mean-square (rms) = 1.1 hildebrands]. We apply the CED method to model the Caltech electronic nose, an array of 20 polymer sensors. Sensors are built with conducting leads connected through thin-film polymers loaded with carbon black. Odorant detection relies on a change in electric resistivity of the polymer film as function of the amount of swelling caused by the odorant compound. The amount of swelling depends upon the chemical composition of the polymer and the odorant molecule. The pattern is unique, and unambiguously identifies the compound. Experimentally determined changes in relative resistivity of seven polymer sensors upon exposure to 24 solvent vapors were modeled with the CED estimated Hansen solubility components. Predictions of polymer sensor responses result in Pearson R2 coefficients between 0.82 and 0.99.

Catalysis research of relevance to carbon management: progress, challenges, and opportunities.

The goal of the "Opportunities for Catalysis Research in Carbon Management" workshop was to review within the context of greenhouse gas/carbon issues the current state of knowledge, barriers to further scientific and technological progress, and basic scientific research needs in the areas of H2 generation and utilization, light hydrocarbon activation and utilization, carbon dioxide activation, utilization, and sequestration, emerging techniques and research directions in relevant catalysis research, and in catalysis for more efficient transportation engines. Several overarching themes emerge from this review. First and foremost, there is a pressing need to better understand in detail the catalytic mechanisms involved in almost every process area mentioned above. This includes the structures, energetics, lifetimes, and reactivities of the species thought to be important in the key catalytic cycles. As much of this type of information as is possible to acquire would also greatly aid in better understanding perplexing, incomplete/inefficient catalytic cycles and in inventing new, efficient ones. The most productive way to attack such problems must include long-term, in-depth fundamental studies of both commercial and model processes, by conventional research techniques and, importantly, by applying various promising new physicochemical and computational approaches which would allow incisive, in situ elucidation of reaction pathways. There is also a consensus that more exploratory experiments, especially high-risk, unconventional catalytic and model studies, should be undertaken. Such an effort will likely require specialized equipment, instrumentation, and computational facilities. The most expeditious and cost-effective means to carry out this research would be by close coupling of academic, industrial, and national laboratory catalysis efforts worldwide. Completely new research approaches should be vigorously explored, ranging from novel compositions, fabrication techniques, reactors, and reaction conditions for heterogeneous catalysts, to novel ligands and ligation geometries (e.g., biomimetic), reaction media, and activation methods for homogeneous ones. The interplay between these two areas involving various hybrid and single-site supported catalyst systems should also be productive. Finally, new combinatorial and semicombinatorial means to rapidly create and screen catalyst systems are now available. As a complement to the approaches noted above, these techniques promise to greatly accelerate catalyst discovery, evaluation, and understanding. They should be incorporated in the vigorous international research effort needed in this field.

Chelators for radioimmunotherapy: I. NMR and ab initio calculation studies on 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr).

This work describes the modification of the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' "-tetraacetic acid (DOTA) to improve the rate of metal loading for radioimmunotherapy applications. Previous ab initio calculations predicted that the compounds 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr) have a ca. 2000-fold improvement in yttrium metal loading rates compared to those of DOTA (Jang, Y. H.; Blanco, M.; Dasgupta, S.; Keire, D. A.; Shively, J. E.; Goddard, W. A., III. J. Am. Chem. Soc. 1999, 121, 6142-6151). In this study, we report the synthesis, purification, (1)H-NMR chemical shift assignments, pK(a) values, metal loading rate measurements, and additional ab initio calculations of these two compounds. The yttrium loading rates of DO3A1Pr are approximately twice those of DOTA, at pH 4.6 and 37 degrees C. The NMR data indicates that the DO4Pr analogue forms a stable type I complex but does not form a type II complex. The new ab initio calculations performed on DO4Pr and DO3A1Pr indicate that the rate-determining step is the deprotonation of the first macrocycle amine proton, not the second proton as assumed in the previous calculations. The new calculations predict an improvement in the rate of metal loading that more closely matches the experimentally observed change in the rate.

Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor.

The prevailing paradigm for G protein-coupled receptors is that each receptor is narrowly tuned to its ligand and closely related agonists. An outstanding problem is whether this paradigm applies to olfactory receptor (ORs), which is the largest gene family in the genome, in which each of 1,000 different G protein-coupled receptors is believed to interact with a range of different odor molecules from the many thousands that comprise "odor space." Insights into how these interactions occur are essential for understanding the sense of smell. Key questions are: (i) Is there a binding pocket? (ii) Which amino acid residues in the binding pocket contribute to peak affinities? (iii) How do affinities change with changes in agonist structure? To approach these questions, we have combined single-cell PCR results [Malnic, B., Hirono, J., Sato, T. & Buck, L. B. (1999) Cell 96, 713-723] and well-established molecular dynamics methods to model the structure of a specific OR (OR S25) and its interactions with 24 odor compounds. This receptor structure not only points to a likely odor-binding site but also independently predicts the two compounds that experimentally best activate OR S25. The results provide a mechanistic model for olfactory transduction at the molecular level and show how the basic G protein-coupled receptor template is adapted for encoding the enormous odor space. This combined approach can significantly enhance the identification of ligands for the many members of the OR family and also may shed light on other protein families that exhibit broad specificities, such as chemokine receptors and P450 oxidases.

Conformation and proton configuration of pyrimidine deoxynucleoside oxidation damage products in water.

Emerging data strongly suggest that the oxidation of DNA bases can contribute to genomic instability. Structural changes to DNA, induced by base oxidation, may reduce the fidelity of DNA replication and interfere with sequence-specific DNA-protein interactions. We have examined the structures of a series of pyrimidine deoxynucleoside oxidation damage products in aqueous solution. The modified nucleosides studied include the deoxynucleoside derivatives of 5-hydroxyuracil, 5-hydroxycytosine, 5-(hydroxymethyl)uracil, 5-(hydroxymethyl)cytosine, 5-formyluracil, and 5-formylcytosine. The influence of base oxidation on ionization constants, sugar conformation, and tautomeric configuration has been determined on the basis of UV, proton, and nitrogen NMR spectra of the (15)N-enriched derivatives. The potential biological consequences of the structural perturbations resulting from base oxidation are discussed.

First principles prediction of protein folding rates.

Experimental studies have demonstrated that many small, single-domain proteins fold via simple two-state kinetics. We present a first principles approach for predicting these experimentally determined folding rates. Our approach is based on a nucleation-condensation folding mechanism, where the rate-limiting step is a random, diffusive search for the native tertiary topology. To estimate the rates of folding for various proteins via this mechanism, we first determine the probability of randomly sampling a conformation with the native fold topology. Next, we convert these probabilities into folding rates by estimating the rate that a protein samples different topologies during diffusive folding. This topology-sampling rate is calculated using the Einstein diffusion equation in conjunction with an experimentally determined intra-protein diffusion constant. We have applied our prediction method to the 21 topologically distinct small proteins for which two-state rate data is available. For the 18 beta-sheet and mixed alpha-beta native proteins, we predict folding rates within an average factor of 4, even though the experimental rates vary by a factor of approximately 4 x 10(4). Interestingly, the experimental folding rates for the three four-helix bundle proteins are significantly underestimated by this approach, suggesting that proteins with significant helical content may fold by a faster, alternative mechanism. This method can be applied to any protein for which the structure is known and hence can be used to predict the folding rates of many proteins prior to experiment.

The topomer-sampling model of protein folding.

Clearly, a protein cannot sample all of its conformations (e.g., approximately 3(100) approximately 10(48) for a 100 residue protein) on an in vivo folding timescale (<1 s). To investigate how the conformational dynamics of a protein can accommodate subsecond folding time scales, we introduce the concept of the native topomer, which is the set of all structures similar to the native structure (obtainable from the native structure through local backbone coordinate transformations that do not disrupt the covalent bonding of the peptide backbone). We have developed a computational procedure for estimating the number of distinct topomers required to span all conformations (compact and semicompact) for a polypeptide of a given length. For 100 residues, we find approximately 3 x 10(7) distinct topomers. Based on the distance calculated between different topomers, we estimate that a 100-residue polypeptide diffusively samples one topomer every approximately 3 ns. Hence, a 100-residue protein can find its native topomer by random sampling in just approximately 100 ms. These results suggest that subsecond folding of modest-sized, single-domain proteins can be accomplished by a two-stage process of (i) topomer diffusion: random, diffusive sampling of the 3 x 10(7) distinct topomers to find the native topomer ( approximately 0.1 s), followed by (ii) intratopomer ordering: nonrandom, local conformational rearrangements within the native topomer to settle into the precise native state.

Effects of pressure on the structure of metmyoglobin: molecular dynamics predictions for pressure unfolding through a molten globule intermediate.

We investigated the pathway for pressure unfolding of metmyoglobin using molecular dynamics (MD) for a range of pressures (0.1 MPa to 1.2 GPa) and a temperature of 300 K. We find that the unfolding of metmyoglobin proceeds via a two-step mechanism native --> molten globule intermediate --> unfolded, where the molten globule forms at 700 MPa. The simulation describes qualitatively the experimental behavior of metmyoglobin under pressure. We find that unfolding of the alpha-helices follows the sequence of migrating hydrogen bonds (i,i + 4) --> (i,i + 2).

Kinetic steps for alpha-helix formation.

The kinetics of alpha-helix formation in polyalanine and polyglycine eicosamers (20-mers) were examined using torsional-coordinate molecular dynamics (MD). Of one hundred fifty-five MD experiments on extended (Ala)20 carried out for 0.5 ns each, 129 (83%) formed a persistent alpha-helix. In contrast, the extended state of (Gly)20 only formed a right-handed alpha-helix in two of the 20 MD experiments (10%), and these helices were not as long or as persistent as those of polyalanine. These simulations show helix formation to be a competition between the rates of (a) forming local hydrogen bonds (i.e. hydrogen bonds between any residue i and its i + 2, i + 3, i + 4, or i + 5th neighbor) and (b) forming nonlocal hydrogen bonds (HBs) between residues widely separated in sequence. Local HBs grow rapidly into an alpha-helix; but nonlocal HBs usually retard helix formation by "trapping" the polymer in irregular, "balled-up" structures. Most trajectories formed some nonlocal HBs, sometimes as many as eight. But, for (Ala)20, most of these eventually rearranged to form local HBs that lead to alpha-helices. A simple kinetic model describes the rate of converting nonlocal HBs into alpha-helices. Torsional-coordinate MD speeds folding by eliminating bond and angle degrees of freedom and reducing dynamical friction. Thus, the observed 210 ps half-life for helix formation is likely to be a lower bound on the real rate. However, we believe the sequential steps observed here mirror those of real systems.

Substrate assistance in the mechanism of family 18 chitinases: theoretical studies of potential intermediates and inhibitors.

Based on first principles and molecular mechanics calculations, we conclude that the mechanism of hevamine (a family 18 chitinase) involves an oxazoline ion intermediate stabilized by the neighboring C2' acetamido group. In this intermediate, the acetamido carbonyl oxygen atom forms a covalent bond to C1' of N-acetyl-glucosamine and has a transferred positive charge from the pyranose ring onto the acetamido nitrogen atom, leading to an anchimeric stabilization of 38.1 kcal/mol when docked with hevamine. This double displacement mechanism involving an oxazoline intermediate distinguishes the family 18 chitinase (which have one acidic residue near the active site) from family 19 chitinase and from hen egg-white lysozyme, which have two acidic residues near the active site. The structural and electronic properties of the oxazoline intermediate are similar to the known chitinase inhibitor allosamidin, suggesting that allosamidins act as transition state analogs of an oxazoline intermediate. Structural and electronic features of the oxazoline ion likely to be important in the design of new chitinase inhibitors are discussed.

The role of enzyme distortion in the single displacement mechanism of family 19 chitinases.

By using molecular dynamics simulations, we have examined the binding of a hexaNAG substrate and two potential hydrolysis intermediates (an oxazoline ion and an oxocarbenium ion) to a family 19 barley chitinase. We find the hexaNAG substrate binds with all sugars in a chair conformation, unlike the family 18 chitinase which causes substrate distortion. Glu 67 is in a position to protonate the anomeric oxygen linking sugar residues D and E whereas Asn 199 serves to hydrogen bond with the C2' N-acetyl group of sugar D, thus preventing the formation of an oxazoline ion intermediate. In addition, Glu 89 is part of a flexible loop region allowing a conformational change to occur within the active site to bring the oxocarbenium ion intermediate and Glu 89 closer by 4-5 A. A hydrolysis product with inversion of the anomeric configuration occurs because of nucleophilic attack by a water molecule that is coordinated by Glu 89 and Ser 120. Issues important for the design of inhibitors specific to family 19 chitinases over family 18 chitinases also are discussed.

The pentamer channel stiffening model for drug action on human rhinovirus HRV-1A.

Development of effective drugs against the rhinovirus (HRV) responsible for the common cold remains a challenge because there are over 100 serotypes. This process could be significantly aided by an understanding of the atomistic mechanism by which such drugs work. We suggest that the most effective drugs against HRV-1A act by stiffening the pentamer channel of the viral coat through which the RNA is released, preventing the steps leading to uncoating. Using molecular dynamics methods we tested this Pentamer Channel Stiffening Model (PCSM) by examining the changes in strain energy associated with opening the pentamer channel through which the RNA is released. We find that the PCSM strain correlates well with the effectiveness of the WIN (Sterling-Winthrop) drugs for HRV-1A. To illustrate the use of the PCSM to predict new drugs and to prioritize experimental tests, we tested three modifications of the WIN drugs that are predicted to be nearly as effective (for HRV-1A) as the best current drug.

Prediction of polyelectrolyte polypeptide structures using Monte Carlo conformational search methods with implicit solvation modeling.

Many interesting proteins possess defined sequence stretches containing negatively charged amino acids. At present, experimental methods (X-ray crystallography, NMR) have failed to provide structural data for many of these sequence domains. We have applied the dihedral probability grid-Monte Carlo (DPG-MC) conformational search algorithm to a series of N- and C-capped polyelectrolyte peptides, (Glu)20, (Asp)20, (PSer)20, and (PSer-Asp)10, that represent polyanionic regions in a number of important proteins, such as parathymosin, calsequestrin, the sodium channel protein, and the acidic biomineralization proteins. The atomic charges were estimated from charge equilibration and the valence and van der Waals parameters are from DREIDING. Solvation of the carboxylate and phosphate groups was treated using sodium counterions for each charged side chain (one Na+ for COO-; two Na for CO(PO3)-2) plus a distance-dependent (shielded) dielectric constant, epsilon = epsilon 0 R, to simulate solvent water. The structures of these polyelectrolyte polypeptides were obtained by the DPG-MC conformational search with epsilon 0 = 10, followed by calculation of solvation energies for the lowest energy conformers using the protein dipole-Langevin dipole method of Warshel. These calculations predict a correlation between amino acid sequence and global folded conformational minima: 1. Poly-L-Glu20, our structural benchmark, exhibited a preference for right-handed alpha-helix (47% helicity), which approximates experimental observations of 55-60% helicity in solution. 2. For Asp- and PSer-containing sequences, all conformers exhibited a low preference for right-handed alpha-helix formation (< or = 10%), but a significant percentage (approximately 20% or greater) of beta-strand and beta-turn dihedrals were found in all three sequence cases: (1) Aspn forms supercoil conformers, with a 2:1:1 ratio of beta-turn:beta-strand:alpha-helix dihedral angles; (2) PSer20 features a nearly 1:1 ratio of beta-turn:beta-sheet dihedral preferences, with very little preference for alpha-helical structure, and possesses short regions of strand and turn combinations that give rise to a collapsed bend or hairpin structure; (3) (PSer-Asp)10 features a 3:2:1 ratio of beta-sheet:beta-turn:alpha-helix and gives rise to a superturn or C-shaped structure.